Amine derivative

ABSTRACT

The present invention provides a compound represented by the formula  
                 
wherein 
     Ar 1  is a cyclic group optionally having substituent(s);    R is a hydrogen atom, an optionally halogenated C 1-6  alkyl, a phenyl optionally having substituent(s) or a pyridyl optionally having substituent(s);    Ra 1 , Ra 2 , Ra 3  and Ra 4  are the same or different and each is a hydrogen atom, an optionally halogenated C 1-6  alkyl or the like; Ar is a monocyclic aromatic ring optionally having substituent(s); Y is an optionally halogenated alkylene group; and    R 1  and R 2  are (1) the same or different and each is a hydrogen atom or a C 1-6  alkyl, (2) R 1  and R 2  form a nitrogen-containing heterocycle optionally having substituent(s) together with the adjacent nitrogen atom, or (3) R 1  and Y form a nitrogen-containing heterocycle optionally having substituent(s) together with the adjacent nitrogen atom, and R 2  is a hydrogen atom or a C 1-6  alkyl;    provided that when the nitrogen-containing heterocycle formed by R 1  and R 2  together with the adjacent nitrogen atom is a piperazine, or when R is a C 1-4  alkyl, Ar 1  is a cyclic group having substituent(s), or a salt thereof, having a melanin-concentrating hormone antagonistic action and useful as an agent for the prophylaxis or treatment of obesity and the like.

TECHNICAL FIELD

The present invention relates to an amine derivative having amelanin-concentrating hormone (hereinafter sometimes to be abbreviatedas MCH) antagonistic action and useful as an agent for the prophylaxisor treatment of obesity and the like.

BACKGROUND ART

Feeding behavior is an indispensable action for many organisms includinghumans. An abnormality in feeding behavior causes deviation from normallife support activities, which in most cases results in diseases. Alongwith the recent changes in feeding environments, obesity is becoming asocial problem. It is widely known that obesity is not only a seriousrisk factor of life-style related diseases, such as diabetes,hypertension, arteriosclerosis and the like, but also causes arthritisand pain resulting from an excessive burden on knee joints etc. due toincreased body weight. In addition, the dieting boom and the like haveincreased the potential population that desires weight loss. There aremany reports on eating disorders, such as hyperphagia and the like, dueto neuropathy and the like, which are genetic or caused by stress.

Consequently, the development and investigation of agents for theprophylaxis or treatment of obesity or feeding deterrents started sometime ago, and mazindol has been on the market as a centrally actinganorectic agent.

Along therewith, a number of appetite-regulating factors represented byleptin have been found in recent years, and new anti-obesity agents andanorectic agents that suppress the activity of such appetite-regulatingfactors have been developed. Among others, a melanin-concentratinghormone is a hormone derived from hypothalamus and known to have anappetite stimulating action. Furthermore, MCH knockout mouse has beenreported to show significantly decreased food intake and be lean, ascompared to normal mouse, though normal in daily behavior [see Nature,vol. 396, p. 670, 1998]. From the foregoing, an MCH antagonist, oncecompleted, is expected to be a superior anorectic agent or anti-obesityagent.

On the other hand, the following compounds are known as aminederivatives.

1) As β amyloid protein production and secretion inhibitor, a compoundrepresented by the formula:

wherein

-   Ar is an aromatic group optionally having substituent(s);-   X and Y are the same or different and each is a divalent group    selected from —O—, —S—, —CO—, —SO—, —SO₂—, —NR⁸—, —CONR⁸—, —SO₂NR⁸—    and —COO— (R⁸ is a hydrogen atom, a hydrocarbon group optionally    having substituent(s) or an acyl) or a divalent C₁₋₆ aliphatic    hydrocarbon group optionally having one or two groups from these    divalent groups;-   R¹ and R² are a hydrogen atom or a C₁₋₆ alkyl optionally having    substituent(s), or R¹ and R² may form a nitrogen-containing    heterocycle optionally having substituent(s) together with the    adjacent nitrogen atom; and-   ring A is a monocyclic aromatic ring optionally further having    substituent(s),-   or a salt thereof, has been reported (see WO00/31021).

2) As MCH antagonist, a compound represented by the formula:

-   wherein Ar¹ is a cyclic group optionally having substituent(s);-   X is a spacer having 1 to 6 atoms in a main chain;-   Y is bond or a spacer having 1 to 6 atoms in a main chain;-   Ar is a monocyclic aromatic ring optionally fused with a 4- to    8-membered non-aromatic ring, which optionally further has    substituent(s); and-   R¹ and R² are the same or different and each is a hydrogen atom or a    hydrocarbon group optionally having substituent(s), or R¹ and R² may    form a nitrogen-containing heterocycle optionally having    substituent(s) together with the adjacent nitrogen atom, R² may form    a spiro ring together with Ar, or R² may form a nitrogen-containing    heterocycle optionally having substituent(s) together with the    adjacent nitrogen atom and Y,-   or a salt thereof, has been reported (see WO01/21577).

3) As MCH antagonist, a compound represented by the formula:

wherein

-   Ar¹ is a cyclic group optionally having substituent(s);-   X and Y are the same or different and each is a spacer having 1 to 6    atoms in a main chain;-   Ar is a fused polycyclic aromatic ring optionally having    substituent(s); and-   R¹ and R² are the same or different and each is a hydrogen atom or a    hydrocarbon group optionally having substituent(s), or R¹ and R² may    form a nitrogen-containing heterocycle optionally having    substituent(s) together with the adjacent nitrogen atom, R² may form    a nitrogen-containing heterocycle optionally having substituent(s)    together with the adjacent nitrogen atom and Y, or R² may form a    fused ring together with the adjacent nitrogen atom, Y and Ar,-   or a salt thereof, has been reported (see WO01/82925).

4) As cathepsin B substrate, a compound represented by the formula:Bz—X—Arg—MCA (Bz is a benzoyl group, MCA is a 7-methylcoumarinamido andX is a 4-aminomethyl-phenylalanine, a 4-guanidine-phenylalanine, a4-aminomethyl-N-isopropylphenylalanine or the like), has been described(see Biochimica et Biophysica Acta, vol. 1547, pages 82-94, 2001).

5) It has been reported that an aminoalcohol derivative having ahypotensive, analgesic, antiinflammatory or psychotropic action isproduced by the reaction shown in the scheme:

wherein

-   A is a straight chain or branched alkylene having 2 to 5 carbon    atoms;-   Y is —N(R⁴)(R⁵) [R⁴, R⁵ are the same or different and each is a    hydrogen, a lower alkyl or an acyl] or —OR⁶ [R⁶ is a hydrogen, a    lower alkyl, an aryl or an acyl];-   R¹ is a hydrogen or a lower alkyl;-   R² and R³ are the same or different and each is a hydrogen, a lower    alkyl or an aralkyl, or a group forming a heterocycle together with    the adjacent nitrogen atom; and-   X is a hydrogen, a halogen or a lower alkyl (see JP51-141829A).

6) As an aminoalcohol derivative having a hypotensive, analgesic orpsychotropic action, a compound represented by the formula:

wherein

-   R is an amino, a hydroxyl group, a lower alkoxy, an acyloxy, an    aroyloxy, an acylamino or an aroylamino;-   A is a lower alkylene;-   R¹ is a hydrogen or an acyl;-   R² is a hydrogen or a lower alkyl; and-   ring P is a group forming, together with the nitrogen atom, a    piperidine, a 4-substituted piperidine or a 4-substituted    piperazine,-   or an acid addition salt thereof, has been reported (see    JP61-2663A).

7) As an aminoketone derivative having a hypotensive, analgesic,antiinflammatory or psychotropic action, a compound represented by theformula:

wherein

-   A is a straight chain or branched alkylene having 2 to 5 carbon    atoms;-   W is —N(R²)(R⁸) [R² is a hydrogen or a lower alkyl; and R⁸ is a    hydrogen or an acyl] or —OR⁴ [R⁴ is a hydrogen, a lower alkyl, an    aryl or an acyl];-   R¹ is a hydrogen or a lower alkyl;-   R⁵ and R⁶ are the same or different and each is a hydrogen, a lower    alkyl or an aralkyl, or form, together with the adjacent nitrogen    atom, a 1-pyrrolidinyl, a piperidino, a    4-carbamoyl-4-piperidinopiperidino, a    4-hydroxy-4-(p-tolyl)piperidino, a morpholino or a    4-substituted-1-piperazinyl; and-   X is a hydrogen, a halogen or a lower alkyl, or a salt thereof, has    been disclosed (see JP51-141831A).

8) As a TNF-α-production suppressor and/or IL-10 production promoter, acompound represented by the formula:

wherein

-   Q is a group: X—Y [X is an amino optionally having substituent(s) or    the like; and Y is an alkylene], or a heterocycle;-   Z is an alkylene or the like;-   R¹ and R² are a hydrogen, a halogen, an alkyl, an amino, a nitro or    a hydroxyl group; and-   R³ is a lower alkyl, an aryl, an aralkyl, a heteroaryl or a    heteroaralkyl,-   or a salt thereof, has been reported (see JP2001-72660A).

9) A compound useful for the treatment of inflammation, allergy and thelike, which is represented by the formula:

wherein

-   R₁ is a hydrogen, a halo, a cyano, a cyanoalkyl, an alkyl, an    alkoxy, a phenoxy, a phenyl, an alkoxycarbonyl, —NR₁₃R₁₄,    —N(R₁₅)SO₂R₁₆, a halogenated alkoxy, a halogenated alkyl, an    arylalkoxy, a hydroxyl group, a phenylalkyl, an alkoxycarbonylvinyl,    —S(O)nR₇, an alkoxycarbonylalkyl, a carboxyalkyl, —CONR₁₁R₁₂, a    carbamoylvinyl, —OSO₂R₂₁, a 4,5-dihydrothiazol-2-yl, a    4,4-dimethyl-2-oxazolin-2-yl or —NR₆₀R₆₁; or R₁ is —(O)z—L₃G [z is 0    or 1; L₃ is a C₁₋₄ alkylene chain; and G is —NR₂₂R₂₃, —S(O)mR₂₆,    —CONR₂₇R₂₈ or —OR₂₉];-   R₂ and R₃ are independently a hydrogen, a halo, an alkyl, an alkoxy,    —NR₁₃R₁₄, a halogenated alkoxy, a halogenated alkyl, a hydroxyl    group, —S(O)nR₇ or —NR₆₀R₆₁;-   L₁ is bond, an alkylene, a cycloalkylene or a cycloalkylidene;-   T is bond, O, S, SO₂, a carbonyl group or a 1,3-dioxolan-2-ylidene;-   L₂ is a alkylene, a cycloalkylene or a cycloalkylidene;-   R₆ is a hydrogen or an alkyl (optionally substituted by an    alkoxycarbonyl or a hydroxyl group);-   Q is a C₁₋₉ alkylene chain (optionally substituted by an alkyl or a    hydroxyl group); and-   Y is an optionally substituted imidazole ring,-   or a salt thereof, has been reported (see WO95/00493).

DISCLOSURE OF THE INVENTION

The present invention aims at providing a compound having amelanin-concentrating hormone antagonistic action, which is useful as anagent for the prophylaxis or treatment of obesity and the like.

As a result of the intensive studies of compounds having an MCHantagonistic action, the present inventors have found that a compoundrepresented by the formula:

wherein

-   Ar¹ is a cyclic group optionally having substituent(s);-   R is a hydrogen atom, an optionally halogenated C₁₋₆ alkyl, a phenyl    optionally having substituent(s) or a pyridyl optionally having    substituent(s);-   Ra¹, Ra², Ra³ and Ra⁴ are the same or different and each is a    hydrogen atom, an optionally halogenated C₁₋₆ alkyl, a phenyl    optionally having substituent(s), a halogen atom, a pyridyl    optionally having substituent(s), a cyano, an optionally halogenated    C₁₋₆ alkoxy, an optionally halogenated C₁₋₆ alkylthio, an amino, a    mono- or di- C₁₋₆ alkylamino, a formyl, an optionally halogenated    C₁₋₆ alkyl-carbonyl or an optionally halogenated C₁₋₆ alkylsulfonyl;-   Ar is a monocyclic aromatic ring optionally having substituent(s);-   Y is an optionally halogenated alkylene group; and-   R¹ and R² are (1) the same or different and each is a hydrogen atom    or a C₁₋₆ alkyl, (2) R¹ and R² form a nitrogen-containing    heterocycle optionally having substituent(s) together with the    adjacent nitrogen atom, or (3) R¹ and Y form a nitrogen-containing    heterocycle optionally having substituent(s) together with the    adjacent nitrogen atom, and R² is a hydrogen atom or a C₁₋₆ alkyl;-   provided that when the nitrogen-containing heterocycle formed by R¹    and R² together with the adjacent nitrogen atom is a piperazine, or    when R is a C₁₋₄ alkyl, Ar¹ is a cyclic group having substituent(s),-   or a salt thereof [hereinafter sometimes to be abbreviated as    compound (I)], which is constituted by introducing a group    represented by the formula:-    wherein the symbols in the formula are as defined above, into a    compound represented by the formula:-    wherein the symbols in the formula are as defined above, has a    superior MCH antagonistic action, which resulted in the completion    of the present invention.

Accordingly, the present invention relates to

-   1) compound (I);-   2) compound (I) wherein R¹ and R² are the same or different and each    is a hydrogen atom or a C₁₋₆ alkyl, or R¹ and R² form a    nitrogen-containing heterocycle optionally having substituent(s)    together with the adjacent nitrogen atom;-   3) compound (I) wherein Ar¹ is a group represented by the formula:    Ar³—Ar²— (wherein Ar² is a cyclic group optionally having    substituent(s) and Ar³ is an aromatic group optionally having    substituent(s));-   4) compound (I) wherein R is a hydrogen atom;-   5) compound (I) wherein Ra¹, Ra², Ra³ and Ra⁴ are each a hydrogen    atom;-   6) compound (I) wherein Ar is a benzene ring;-   7) compound (I) wherein Y is a C₁₋₆ alkylene group;-   8) compound (I) wherein R¹ and R² form a nitrogen-containing    heterocycle optionally having substituent(s) together with the    adjacent nitrogen atom;-   9) compound (I) of the aforementioned 8), wherein the    nitrogen-containing heterocycle is a piperidine, a pyrrolidine, a    hexamethylenimine, a morpholine or a thiomorpholine;-   10) compound (I) which is    4′-chloro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide;-   4′-chloro-3-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide;-   4′-chloro-N-(2-{4-[1-(1-pyrrolidinyl)propyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide;-   4-(cyclopropylmethoxy)-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide;-   4′-methoxy-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide;-   N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(cyclopropylmethoxy)benzamide;-   N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(2-cyclopropylethoxy)benzamide;-   4′-chloro-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide;    or-   4-(2-cyclopropylethoxy)-N-(2-{4-[1-(1)-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide;-   11) a pharmaceutical agent which comprises compound (I) or a prodrug    thereof;-   12) the pharmaceutical agent of the aforementioned 11), which is a    melanin-concentrating hormone antagonist;-   13) the pharmaceutical agent of the aforementioned 11), which is an    agent for the prophylaxis or treatment of a disease caused by a    melanin-concentrating hormone;-   14) the pharmaceutical agent of the aforementioned 11), which is an    agent for the prophylaxis or treatment of obesity;-   15) the pharmaceutical agent of the aforementioned 11), which is a    feeding deterrent;-   16) the pharmaceutical agent of the aforementioned 11), which is an    agent for the prophylaxis or treatment of depression;-   17) the pharmaceutical agent of the aforementioned 11), which is an    agent for the prophylaxis or treatment of anxiety;-   18) use of compound (I) or a prodrug thereof for the production of a    melanin-concentrating hormone antagonist;-   19) a method for antagonizing a melanin-concentrating hormone    receptor in a mammal, which comprises administering an effective    amount of compound (I) or a prodrug thereof to said mammal;-   20) use of compound (I) or a prodrug thereof for the production of    an agent for the prophylaxis or treatment of a disease caused by a    melanin-concentrating hormone;-   21) a method for preventing or treating a disease caused by a    melanin-concentrating hormone in a mammal, which comprises    administering an effective amount of compound (I) or a prodrug    thereof to said mammal;-   22) use of compound (I) or a prodrug thereof for the production of    an agent for the prophylaxis or treatment of obesity;-   23) a method for preventing or treating obesity in a mammal, which    comprises administering an effective amount of compound (I) or a    prodrug thereof to said mammal;-   24) use of compound (I) or a prodrug thereof for the production of a    feeding deterrent;-   25) a method for suppressing food intake by a mammal, which    comprises administering an effective amount of compound (I) or a    prodrug thereof to said mammal;-   26) use of compound (I) or a prodrug thereof for the production of    an agent for the prophylaxis or treatment of depression;-   27) a method for preventing or treating depression in a mammal,    which comprises administering an effective amount of compound (I) or    a prodrug thereof to said mammal;-   28) use of compound (I) or a prodrug thereof for the production of    an agent for the prophylaxis or treatment of anxiety;-   29) a method for preventing or treating anxiety in a mammal, which    comprises administering an effective amount of compound (I) or a    prodrug thereof to said mammal;    and the like.

The definition of each substituent of compound (I) is described indetail in the following.

As the “cyclic group” of the “cyclic group optionally havingsubstituent(s)” for Ar¹, an aromatic group, a non-aromatic cyclichydrocarbon group, a non-aromatic heterocyclic group and the like can bementioned.

Here, as the “aromatic group”, a monocyclic aromatic group and a fusedpolycyclic aromatic group can be mentioned.

As the monocyclic aromatic group, for example, phenyl and a 5- or6-membered aromatic heterocyclic group can be mentioned.

As the “5- or 6-membered aromatic heterocyclic group”, for example, a 5-or 6-membered aromatic heterocyclic group containing, besides carbonatoms, one or more (e.g., 1 to 3) hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom, and the like can be mentioned.To be specific, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, oxadiazolyl, thiadiazolyl, furazanyl and thelike can be mentioned.

As specific examples of the “monocyclic aromatic group”, phenyl, 2- or3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl,2-, 4- or 5-oxazolyl, 1-, 3- or 4-pyrazolyl, 2-pyrazinyl, 2-, 4- or5-pyrimidinyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 4-imidazolyl, 3- or4-pyridazinyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-isoxazolyl,1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl and thelike can be mentioned.

The “fused polycyclic aromatic group” is preferably a bicyclic totetracyclic, more preferably bicyclic or tricyclic aromatic group. Asthe “fused polycyclic aromatic group”, for example, a fused polycyclicaromatic hydrocarbon group, a fused polycyclic aromatic heterocyclicgroup and the like can be mentioned.

As the “fused polycyclic aromatic hydrocarbon group”, for example, afused polycyclic (bicyclic or tricyclic) aromatic hydrocarbon grouphaving 9 to 14 carbon atoms (e.g., naphthalenyl, indenyl, fluorenyl,anthracenyl and the like) and the like can be mentioned.

As the “fused polycyclic aromatic heterocyclic group”, for example, a 9-to 14-membered, preferably 9- or 10-membered fused polycyclic(preferably bicyclic or tricyclic) aromatic heterocyclic groupcontaining, besides carbon atoms, one or more (e.g., 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom,and the like can be mentioned. The “fused polycyclic aromaticheterocyclic group” is more preferably a 10-membered fused polycyclicaromatic heterocyclic group.

As specific examples of the “fused polycyclic aromatic heterocyclicgroup”, benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzisothiazolyl, naphtho[2,3-b]thiophenyl, isoquinolyl,quinolyl, indolyl, quinoxalinyl, phenanthridinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl,carbazolyl, β-carbolinyl, acridinyl, phenazinyl, phthalimido,thioxanthenyl and the like can be mentioned.

As specific examples of the “fused polycyclic aromatic group”, 1- or2-naphthyl; 2-, 3-, 4-, 5- or 8-quinolyl; 1-, 3-, 4-, 5-, 6-, 7- or8-isoquinolyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl; 1-, 2-, 4- or5-isoindolyl; 1-, 5- or 6-phthalazinyl; 2-, 3- or 5-quinoxalinyl; 2-,3-, 4-, 5- or 6-benzothienyl; 2-, 3-, 4-, 5- or 6-benzofuranyl; 2-, 4-,5- or 6-benzothiazolyl; 1-, 2-, 4-, 5- or 6-benzimidazolyl and the likecan be mentioned.

As the “non-aromatic cyclic hydrocarbon group”, for example, a C₃₋₈cycloalkyl, a C₃₋₈ cycloalkenyl and the like can be mentioned.

Here, as specific examples of the C₃₋₈ cycloalkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and thelike can be mentioned.

As specific examples of the C₃₋₈ cycloalkenyl, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyland the like can be mentioned.

As the “non-aromatic heterocyclic group”, for example, a monocyclicnon-aromatic heterocyclic group, a fused polycyclic non-aromaticheterocyclic group and the like can be mentioned.

As the “monocyclic non-aromatic heterocyclic group”, for example, a 5-to 8-membered monocyclic non-aromatic heterocyclic group containing,besides carbon atoms, one or more (e.g., 1 to 3) hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom, and the like canbe mentioned. To be specific, tetrahydrothiophenyl, tetrahydrofuranyl,pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl,tetrahydrothiazolyl, tetrahydroisothiazolyl, tetrahydrooxazolyl,tetrahydroisoxazolyl, piperidinyl, tetrahydropyridyl, dihydropyridyl,piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl,tetrahydropyridazinyl, hexamethyleniminyl, dioxanyl and the like can bementioned.

The “fused polycyclic non-aromatic heterocyclic group” is preferably abicyclic to tetracyclic, more preferably bicyclic or tricyclicnon-aromatic heterocyclic group. As the “fused polycyclic non-aromaticheterocyclic group”, for example, a 9- to 14-membered, preferably 9- or10-membered fused polycyclic (preferably bicyclic or tricyclic)non-aromatic heterocyclic group containing, besides carbon atoms, one ormore (e.g., 1 to 4) hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom, and the like can be mentioned. To be specific,dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl,dihydrobenzothiazolyl, dihydrobenzisothiazolyl,dihydronaphtho[2,3-b]thiophenyl, tetrahydroisoquinolyl,tetrahydroquinolyl, indolinyl, isoindolinyl, tetrahydroquinoxalinyl,tetrahydrophenanthridinyl, hexahydrophenothiazinyl,hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl,tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl,tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl,tetrahydrothioxanthenyl, dihydrobenzopyranyl, tetrahydrobenzoxepinyl andthe like can be mentioned.

The “cyclic group” for Ar¹ is preferably phenyl, a 5- or 6-memberedaromatic heterocyclic group, a 5- to 8-membered monocyclic non-aromaticheterocyclic group and the like, more preferably phenyl, pyridyl,piperidinyl and the like.

As the “substituent” of the “cyclic group optionally havingsubstituent(s)” for Ar¹, for example, a halogen atom (e.g., fluorine,chlorine, bromine, iodine and the like), a C₁₋₃ alkylenedioxy (e.g.,methylenedioxy, ethylenedioxy and the like), a nitro, a cyano, anoptionally halogenated C₁₋₁₀ alkyl, a hydroxy-C₁₋₁₀ alkyl (e.g.,hydroxymethyl, hydroxyethyl), a C₆₋₁₄ aryloxy-C₁₋₆ alkyl (e.g.,phenoxymethyl and the like), a C₁₋₆ alkyl-C₆₋₁₄ aryl-C₂₋₆ alkenyl (e.g.,methylphenylethenyl and the like), an optionally halogenated C₁₋₁₀alkoxy, an optionally halogenated C₁₋₁₀ alkylthio, a C₇₋₁₉ aralkyloptionally having substituent(s), a hydroxy, a C₆₋₁₄ aryloxy optionallyhaving substituent(s), a C₇₋₁₉ aralkyloxy optionally havingsubstituent(s), an amino, an amino-C₁₋₁₀ alkyl (e.g., aminomethyl,aminoethyl, aminopropyl, aminobutyl and the like), a mono- or di-C₁₋₁₀alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino,butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino,ethylmethylamino and the like), a mono- or di-C₁₋₁₀ alkylamino-C₁₋₆alkyl (e.g., methylaminomethyl, ethylaminomethyl, propylaminomethyl,isopropylaminoethyl, butylaminoethyl, dimethylaminomethyl,diethylaminomethyl, dipropylaminomethyl, diisopropylaminoethyl,dibutylaminoethyl and the like), an aromatic group optionally havingsubstituent(s), a non-aromatic group optionally having substituent(s), aC₃₋₆ cycloalkyl-C₁₋₆ alkyl optionally having substituent(s), a C₃₋₆cycloalkyl-C₁₋₆ alkoxy optionally having substituent(s), a C₁₋₆alkoxy-C₁₋₆ alkoxy, an acyl, an acylamino, an acyloxy, an acyl-C₁₋₆alkyl, an acylamino-C₁₋₆ alkyl, an acyloxy-C₁₋₆ alkyl and the like canbe mentioned.

The “cyclic group” for Ar¹ optionally has 1 to 5, preferably 1 to 3,substituents mentioned above at substitutable positions on the cyclicgroup. When the number of the substituents is not less than 2,respective substituents may be the same or different.

As the aforementioned “optionally halogenated C₁₋₁₀ alkyl”, for example,a C₁₋₁₀ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl andthe like) optionally having 1 to 5, preferably 1 to 3, halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like) can bementioned. As specific examples, methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl, heptyl, octyl, nonyl, decyl and the like can bementioned.

As the aforementioned “optionally halogenated C₁₋₁₀ alkoxy”, forexample, a C₁₋₁₀ alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy,pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and thelike) optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like) and the like can bementioned. As specific examples, for example, methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy,isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and thelike can be mentioned.

As the aforementioned “optionally halogenated C₁₋₁₀ alkylthio”, forexample, a C₁₋₁₀ alkylthio (e.g., methylthio, ethylthio, propylthio,isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio,hexylthio, heptylthio, octylthio, nonylthio, decylthio and the like)optionally having 1 to 5, preferably 1 to 3, halogen atoms (e.g.,fluorine, chlorine, bromine, iodine and the like) and the like can bementioned. As specific examples, for example, methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,hexylthio, heptylthio, octylthio, nonylthio, decylthio and the like canbe mentioned.

As the “C₇₋₁₉ aralkyl” of the aforementioned “C₇₋₁₉ aralkyl optionallyhaving substituent(s)”, for example, benzyl, phenethyl, diphenylmethyl,triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl,3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and the like can bementioned.

As the “C₆₋₁₄ aryloxy” of the aforementioned “C₆₋₁₄ aryloxy optionallyhaving substituent(s)”, for example, phenyloxy, 1-naphthyloxy,2-naphthyloxy and the like can be mentioned.

As the “C₇₋₁₉ aralkyloxy” of the aforementioned “C₇₋₁₉ aralkyloxyoptionally having substituent(s)”, for example, benzyloxy, phenethyloxy,diphenylmethyloxy, triphenylmethyloxy, 1-naphthylmethyloxy,2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy,4-phenylbutyloxy, 5-phenylpentyloxy and the like can be mentioned.

As the “aromatic group” of the aforementioned “aromatic group optionallyhaving substituent(s)”, the “aromatic group” exemplified for theaforementioned Ar¹ can be mentioned. The “aromatic group” is preferablyphenyl, naphthyl, a 5- or 6-membered aromatic heterocyclic group, a 9-or 10-membered fused polycyclic aromatic heterocyclic group and thelike, more preferably phenyl, a 5- or 6-membered aromatic heterocyclicgroup and the like. Of these, phenyl, pyridyl and the like arepreferable.

As the “non-aromatic group” of the aforementioned “non-aromatic groupoptionally having substituent(s)”, the “non-aromatic cyclic hydrocarbongroup” and the “non-aromatic heterocyclic group” exemplified for theaforementioned Ar¹ can be mentioned. The “non-aromatic group” ispreferably a C₃₋₈ cycloalkyl, a 5- to 8-membered monocyclic non-aromaticheterocyclic group and the like, more preferably cyclohexyl and thelike.

As the “C₃₋₆ cycloalkyl-C₁₋₆ alkyl” of the aforementioned “C₃₋₆cycloalkyl-C₁₋₆ alkyl optionally having substituent(s)”, for example,cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl,cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl,cyclohexylpropyl and the like can be mentioned.

As the “C₃₋₆ cycloalkyl-C₁₋₆ alkoxy” of the aforementioned “C₃₋₆cycloalkyl-C₁₋₆ alkoxy optionally having substituent(s)”, for example,cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy,cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy,cyclohexylmethoxy, cyclohexylethoxy, cyclohexylpropoxy and the like canbe mentioned.

As the aforementioned “C₁₋₆ alkoxy-C₁₋₆ alkoxy”, for example,methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the likecan be mentioned.

As the “substituent” of the aforementioned “C₇₋₁₉ aralkyl optionallyhaving substituent(s)”, “C₆₋₁₄ aryloxy optionally havingsubstituent(s)”, “C₇₋₁₉ aralkyloxy optionally having substituent(s)”,“aromatic group optionally having substituent(s)”, “non-aromatic groupoptionally having substituent(s)”, “C₃₋₆ cycloalkyl-C₁₋₆ alkyloptionally having substituent(s)” and “C₃₋₆ cycloalkyl-C₁₋₆ alkoxyoptionally having substituent(s)”, for example, a halogen atom (e.g.,fluorine, chlorine, bromine, iodine and the like), a C₁₋₃ alkylenedioxy(e.g., methylenedioxy, ethylenedioxy and the like), a nitro, a cyano, anoptionally halogenated C₁₋₁₀ alkyl, a hydroxy-C₁₋₁₀ alkyl (e.g.,hydroxymethyl, hydroxyethyl), an optionally halogenated C₃₋₆ cycloalkyl,an optionally halogenated C₁₋₁₀ alkoxy, an optionally halogenated C₁₋₁₀alkylthio, a hydroxy, an amino, a mono- or di-C₁₋₁₀ alkylamino (e.g.,methylamino, ethylamino, propylamino, isopropylamino, butylamino,dimethylamino, diethylamino, dipropylamino, dibutylamino,ethylmethylamino and the like), an amino-C₁₋₁₀ alkyl (e.g., aminomethyl,aminoethyl, aminopropyl, aminobutyl and the like), a mono- or di-C₁₋₁₀alkylamino-C₁₋₆ alkyl (e.g., methylaminomethyl, ethylaminomethyl,propylaminomethyl, isopropylaminoethyl, butylaminoethyl,dimethylaminomethyl, diethylaminomethyl, dipropylaminomethyl,diisopropylaminoethyl, dibutylaminoethyl and the like), a formyl, acarboxy, a carbamoyl, a thiocarbamoyl, an optionally halogenated C₁₋₆alkyl-carbonyl, a C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like), a 5-or 6-membered heterocyclylcarbonyl, a mono- or di-C₁₋₆ alkyl-carbamoyl(e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl, ethylmethylcarbamoyl and the like), a 5- or 6-memberedheterocyclylcarbamoyl, a carbamoyl-C₁₋₆ alkyl (e.g., carbamoylmethyl,carbamoylethyl, carbamoylpropyl and the like), a mono- or di-C₁₋₆alkyl-carbamoyl-C₁₋₆ alkyl (e.g., methylcarbamoylmethyl,methylcarbamoylethyl, methylcarbamoylpropyl, dimethylcarbamoylmethyl,dimethylcarbamoylethyl, dimethylcarbamoylpropyl, ethylcarbamoylmethyl,ethylcarbamoylethyl, ethylcarbamoylpropyl, diethylcarbamoylmethyl,diethylcarbamoylethyl, diethylcarbamoylpropyl and the like), a 5- or6-membered heterocyclylcarbonyl-C₁₋₆ alkyl, a 5- or 6-memberedheterocyclylcarbamoyl-C₁₋₆ alkyl, an optionally halogenated C₁₋₆alkylsulfonyl, a formylamino, an optionally halogenated C₁₋₆alkyl-carboxamido, a C₁₋₆ alkoxy-carboxamido (e.g., methoxycarboxamido,ethoxycarboxamido, propoxycarboxamido, butoxycarboxamido and the like),a C₁₋₆ alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylaminoand the like), a C₁₋₆ alkyl-carbonyloxy (e.g., acetoxy, propanoyloxy andthe like), a C₁₋₆ alkoxy-carbonyloxy (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like),a mono- or di-C₁₋₆ alkyl-carbamoyloxy (e.g., methylcarbamoyloxy,ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy and thelike), a mono- or di-C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkoxy (e.g.,methylcarbamoylmethoxy, ethylcarbamoylmethoxy, dimethylcarbamoylmethoxy,diethylcarbamoylmethoxy and the like), a 5- or 6-membered non-aromaticheterocyclic group (e.g., pyrrolidinyl, piperidinyl and the like) andthe like can be mentioned. The number of the substituents is, forexample, 1 to 5, preferably 1 to 3. When the number of the substituentsis not less than 2, respective substituents may be the same ordifferent.

Here, as the “optionally halogenated C₁₋₁₀ alkyl”, “optionallyhalogenated C₁₋₁₀ alkoxy” and “optionally halogenated C1-10 alkylthio”,those exemplified as the “substituent” of the “cyclic group optionallyhaving substituent(s)” for the aforementioned Ar¹ can be usedrespectively.

As the aforementioned “optionally halogenated C₃₋₆ cycloalkyl”, forexample, a C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like) optionally having 1 to 5, preferably 1 to 3,halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like)and the like can be mentioned. As specific examples, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl,2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the like can bementioned.

As the aforementioned “optionally halogenated C₁₋₆ alkyl-carbonyl”, forexample, a C₁₋₆ alkyl-carbonyl (e.g., acetyl, propanoyl,2-methylpropanoyl, butanoyl, 3-methylbutanoyl, pentanoyl, hexanoyl andthe like) optionally having 1 to 5, preferably 1 to 3, halogen atoms(e.g., fluorine, chlorine, bromine, iodine and the like) and the likecan be mentioned. As specific examples, for example, acetyl,monochloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl,2-methylpropanoyl, butanoyl, 3-methylbutanoyl, pentanoyl, hexanoyl andthe like can be mentioned.

As the “5- or 6-membered heterocyclylcarbonyl” of the aforementioned “5-or 6-membered heterocyclylcarbonyl” and “5- or 6-memberedheterocyclylcarbonyl-C₁₋₆ alkyl”, for example, nicotinoyl,isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl,morpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl and thelike can be mentioned.

As the “5- or 6-membered heterocyclylcarbonyl-C₁₋₆ alkyl”, for example,morpholinocarbonylmethyl, morpholinocarbonylethyl,morpholinocarbonylpropyl, piperidinocarbonylmethyl,piperidinocarbonylethyl, piperidinocarbonylpropyl,1-pyrrolidinylcarbonylmethyl, 1-pyrrolidinylcarbonylethyl,1-pyrrolidinylcarbonylpropyl and the like can be mentioned.

As the “5- or 6-membered heterocyclylcarbamoyl” of the aforementioned“5- or 6-membered heterocyclylcarbamoyl” and “5- or 6-memberedheterocyclylcarbamoyl-C₁₋₆ alkyl”, for example, morpholinocarbamoyl,piperidinocarbamoyl, 1-pyrrolidinylcarbamoyl, 2-pyridylcarbamoyl,3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl,3-thienylcarbamoyl and the like can be mentioned.

As the “5- or 6-membered heterocyclylcarbamoyl-C₁₋₆ alkyl”, for example,morpholinocarbamoylmethyl, morpholinocarbamoylethyl,morpholinocarbamoylpropyl, piperidinocarbamoylmethyl,piperidinocarbamoylethyl, piperidinocarbamoylpropyl,1-pyrrolidinylcarbamoylmethyl, 1-pyrrolidinylcarbamoylethyl,1-pyrrolidinylcarbamoylpropyl and the like can be mentioned.

As the aforementioned “optionally halogenated C₁₋₆ alkylsulfonyl”, forexample, a C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl,tert-butylsulfonyl and the like) optionally having 1 to 5, preferably 1to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine and thelike) and the like can be mentioned. As specific examples, for example,methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl,ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl and the likecan be mentioned.

As the aforementioned “optionally halogenated C₁₋₆ alkyl-carboxamido”,for example, a C₁₋₆ alkyl-carboxamido (e.g., acetamido, propaneamido,butaneamido and the like) optionally having 1 to 5, preferably 1 to 3,halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like)and the like can be mentioned. As specific examples, for example,acetamido, trifluoroacetamido, propaneamido, butaneamido and the likecan be mentioned.

As the “acyl” exemplified as the “substituent” for the aforementionedAr¹, for example, a group represented by the formula: —CO—R³, —CO—OR³,—CO—NR³R⁴, —CS—NR³R⁴, —SO₂—R³, —SO—R³, —PO(—OR³)—OR⁴ or —PO₂—R³ (whereinR³ is (i) a hydrogen atom, (ii) a hydrocarbon group optionally havingsubstituent(s) or (iii) a heterocyclic group optionally havingsubstituent(s); R⁴ is a hydrogen atom or a C₁₋₆ alkyl; or R³ and R⁴optionally form a nitrogen-containing heterocycle optionally havingsubstituent(s) together with the adjacent nitrogen atom), and the likecan be mentioned.

As the “hydrocarbon group” of the “hydrocarbon group optionally havingsubstituent(s)” for R³, for example, a chain or cyclic hydrocarbon group(e.g., an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, anaralkyl, a cycloalkyl-alkyl and the like) and the like can be mentioned.Of these, a chain or cyclic hydrocarbon group having 1 to 19 carbonatoms and the like as shown below are preferable. The cycloalkyl of theabove-mentioned cycloalkyl and cycloalkyl-alkyl is optionally fused witha benzene ring.

-   a) a C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,    isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like);-   b) a C₂₋₆ alkenyl (e.g., vinyl, allyl, isopropenyl, 2-butenyl and    the like);-   c) a C₂₋₆ alkynyl (e.g., ethynyl, propargyl, 2-butynyl and the    like);-   d) a C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,    cyclohexyl and the like) optionally fused with a benzene ring;-   e) a C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-indenyl,    2-anthryl and the like);-   f) a C₇₋₁₉ aralkyl (e.g., benzyl, phenethyl, diphenylmethyl,    triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,    2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and    the like); and-   g) a C₃₋₆ cycloalkyl-C₁₋₆ alkyl (e.g., cyclopropylmethyl,    cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl,    cyclopentylethyl, cyclohexylpropyl and the like) optionally fused    with a benzene ring.

The “hydrocarbon group” is preferably a C₁₋₆ alkyl, a C₆₋₁₄ aryl, aC₇₋₁₉ aralkyl, a C₃₋₆ cycloalkyl optionally fused with a benzene ring, aC₃₋₆ cycloalkyl-C₁₋₆ alkyl optionally fused with a benzene ring and thelike.

As the “substituent” of the aforementioned “hydrocarbon group optionallyhaving substituent(s)”, for example, a halogen atom (e.g., fluorine,chlorine, bromine, iodine and the like), a C₁₋₃ alkylenedioxy (e.g.,methylenedioxy, ethylenedioxy and the like), a nitro, a cyano, anoptionally halogenated C₁₋₁₀ alkoxy, an optionally halogenated C₁₋₁₀alkylthio, a hydroxy, an amino, a mono- or di-C₁₋₁₀ alkylamino (e.g.,methylamino, ethylamino, propylamino, isopropylamino, butylamino,dimethylamino, diethylamino, dipropylamino, dibutylamino,ethylmethylamino and the like), a formyl, a carboxy, carbamoyl,thiocarbamoyl, an optionally halogenated C₁₋₆ alkyl-carbonyl, a C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl and the like), a 5- to 10-membered aromaticheterocyclic group optionally having substituent(s), a C₆₋₁₄aryl-carbonyl optionally having substituent(s), a C₆₋₁₄ aryloxy-carbonyloptionally having substituent(s), a C₇₋₁₉ aralkyloxy-carbonyl optionallyhaving substituent(s), a 5- or 6-membered heterocyclylcarbonyloptionally having substituent(s), a mono- or di-C₁₋₆ alkyl-carbamoyl(e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl, ethylmethylcarbamoyl and the like), a C₆₋₁₄aryl-carbamoyl optionally having substituent(s), a 5- or 6-memberedheterocyclylcarbamoyl optionally having substituent(s), an optionallyhalogenated C₁₋₆ alkylsulfonyl, a C₆₋₁₄ arylsulfonyl optionally havingsubstituent(s), a formylamino, a C₁₋₆ alkyl-carbonyloxy (e.g., acetoxy,propanoyloxy and the like), a C₆₋₁₄ aryl-carbonyloxy optionally havingsubstituent(s), a C₁₋₆ alkoxy-carbonyloxy (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like),a mono- or di-C₁₋₆ alkyl-carbamoyloxy (e.g., methylcarbamoyloxy,ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy and thelike), a C₆₋₁₄ aryl-carbamoyloxy optionally having substituent(s), a 5-or 6-membered heterocyclylcarbonyloxy optionally having substituent(s)and the like can be mentioned. The number of the substituents is, forexample, 1 to 5, preferably 1 to 3. When the number of the substituentsis not less than 2, respective substituents may be the same ordifferent.

Here, as the “optionally halogenated C₁₋₁₀ alkoxy” and “optionallyhalogenated C₁₋₁₀ alkylthio”, those exemplified as the “substituent” ofthe “cyclic group optionally having substituent(s)” for theaforementioned Ar¹ can be used respectively.

As the aforementioned “optionally halogenated C₁₋₆ alkyl-carbonyl” and“optionally halogenated C₁₋₆ alkylsulfonyl”, those exemplified as the“substituent” of the aforementioned “C₇₋₁₉ aralkyl optionally havingsubstituent(s)” can be used respectively.

As the “5- to 10-membered aromatic heterocyclic group” of theaforementioned “5- to 10-membered aromatic heterocyclic group optionallyhaving substituent(s)”, for example, a 5- to 10-membered monocyclic orbicyclic aromatic heterocyclic group containing, besides carbon atoms, 1to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom, can be mentioned. To be specific, for example, 2- or3-thienyl; 2-, 3- or 4-pyridyl; 2- or 3-furyl; 2-, 4- or 5-thiazolyl;2-, 4- or 5-oxazolyl; 1-, 3- or 4-pyrazolyl; 2-pyrazinyl; 2-, 4- or5-pyrimidinyl; 1-, 2- or 3-pyrrolyl; 1-, 2- or 4-imidazolyl; 3- or4-pyridazinyl; 3-isothiazolyl; 3-isoxazolyl; 1,2,4-oxadiazol-5-yl;1,2,4-oxadiazol-3-yl; 2-, 3-, 4-, 5- or 8-quinolyl; 1-, 3-, 4-, 5-, 6-,7- or 8-isoquinolyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl; 1-, 2-, 4- or5-isoindolyl; 1-, 5- or 6-phthalazinyl; 2-, 3- or 5-quinoxalinyl; 2-,3-, 4-, 5- or 6-benzofuranyl; 2-, 4-, 5- or 6-benzothiazolyl; 1-, 2-,4-, 5- or 6-benzimidazolyl and the like can be mentioned.

As the “C₆₋₁₄ aryl-carbonyl” of the aforementioned “C₆₋₁₄ aryl-carbonyloptionally having substituent(s)”, for example, benzoyl, 1-naphthoyl,2-naphthoyl and the like can be mentioned.

As the “C₆₋₁₄ aryloxy-carbonyl” of the aforementioned “C₆₋₁₄aryloxy-carbonyl optionally having substituent(s)”, for example,phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and thelike can be mentioned.

As the “C₇₋₁₉ aralkyloxy-carbonyl” of the aforementioned “C₇₋₁₉aralkyloxy-carbonyl optionally having substituent(s)”, for example,benzyloxycarbonyl, phenethyloxycarbonyl, diphenylmethyloxycarbonyl,triphenylmethyloxycarbonyl, 1-naphthylmethyloxycarbonyl,2-naphthylmethyloxycarbonyl, 2,2-diphenylethyloxycarbonyl,3-phenylpropyloxycarbonyl, 4-phenylbutyloxycarbonyl,5-phenylpentyloxycarbonyl and the like can be mentioned.

As the “5- or 6-membered heterocyclylcarbonyl” of the aforementioned “5-or 6-membered heterocyclylcarbonyl optionally having substituent(s)”,those exemplified as the “substituent” of the aforementioned “C₇₋₁₉aralkyl optionally having substituent(s)” can be used.

As the “C₆₋₁₄ aryl-carbamoyl” of the aforementioned “C₆₋₁₄aryl-carbamoyl optionally having substituent(s)”, for example,phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the likecan be mentioned.

As the “5- or 6-membered heterocyclylcarbamoyl” of the aforementioned“5- or 6-membered heterocyclylcarbamoyl optionally havingsubstituent(s)”, those exemplified as the “substituent” of theaforementioned “C₇₋₁₉ aralkyl optionally having substituent(s)” can beused.

As the “C₆₋₁₄ arylsulfonyl” of the aforementioned “C₆₋₁₄ arylsulfonyloptionally having substituent(s)”, for example, phenylsulfonyl,1-naphthylsulfonyl, 2-naphthylsulfonyl and the like can be mentioned.

As the “C₆₋₁₄ aryl-carbonyloxy” of the aforementioned “C₆₋₁₄aryl-carbonyloxy optionally having substituent(s)”, for example,benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy and the like can bementioned.

As the “C₆₋₁₄ aryl-carbamoyloxy” of the aforementioned “C₆₋₁₄aryl-carbamoyloxy optionally having substituent(s)”, for example,phenylcarbamoyloxy, naphthylcarbamoyloxy and the like can be mentioned.

As the “5- or 6-membered heterocyclylcarbonyloxy” of the aforementioned“5- or 6-membered heterocyclylcarbonyloxy optionally havingsubstituent(s)”, for example, nicotinoyloxy, isonicotinoyloxy,2-thenoyloxy, 3-thenoyloxy, 2-furoyloxy, 3-furoyloxy,morpholinocarbonyloxy, piperidinocarbonyloxy, pyrrolidin-1-ylcarbonyloxyand the like can be mentioned.

As the “substituent” of the aforementioned “5- to 10-membered aromaticheterocyclic group optionally having substituent(s)”, “C₆₋₁₄aryl-carbonyl optionally having substituent(s)”, “C₆₋₁₄ aryloxy-carbonyloptionally having substituent(s)”, “C₇₋₁₉ aralkyloxy-carbonyl optionallyhaving substituent(s)”, “5- or 6-membered heterocyclylcarbonyloptionally having substituent(s)”, “C₆₋₁₄ aryl-carbamoyl optionallyhaving substituent(s)”, “5- or 6-membered heterocyclylcarbamoyloptionally having substituent(s)”, “C₆₋₁₄ arylsulfonyl optionally havingsubstituent(s)”, “C₆₋₁₄ aryl-carbonyloxy optionally havingsubstituent(s)”, “C₆₋₁₄ aryl-carbamoyloxy optionally havingsubstituent(s)” and “5- or 6-membered heterocyclylcarbonyloxy optionallyhaving substituent(s)”, those exemplified as the. “substituent” of theaforementioned “C₇₋₁₉ aralkyl optionally having substituent(s)” can bementioned. The number of the substituents is, for example, 1 to 5,preferably 1 to 3. When the number of the substituents is not less than2, respective substituents may be the same or different.

As the “heterocyclic group” of the “heterocyclic group optionally havingsubstituent(s)” for R³, for example, a 5- to 14-membered (monocyclic,bicyclic or tricyclic) heterocyclic group containing, besides carbonatoms, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atomand an oxygen atom, can be mentioned, preferably (i) a aromaticheterocyclic group, (ii) a 5- to 10-membered non-aromatic heterocyclicgroup, (iii) a 7- to 10-membered crosslinked heterocyclic group and thelike can be mentioned.

Here, as the “aromatic heterocyclic group”, for example, a 5- to14-membered, preferably 5- to 10-membered aromatic heterocyclic groupcontaining, besides carbon atoms, one or more (e.g., 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom,and the like can be mentioned. To be specific, an aromatic heterocyclicgroup such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, oxadiazolyl, thiadiazolyl, furazanyl,benzothienyl, benzofuranyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzisothiazolyl, naphtho[2,3-b]thiophenyl,phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl,4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl,phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalimido and the like, a group formed by condensing such group withone or more (preferably 1 or 2) aromatic rings (e.g., a benzene ringetc.), and the like can be mentioned.

As the “5- to 10-membered non-aromatic heterocyclic group”, for example,pyrrolidinyl, imidazolidinyl, 2- or 4-imidazolinyl, 2-oxazolinyl,oxazolidinyl, 2- or 3-pyrazolinyl, pyrazolidinyl, 2-thiazolinyl,piperidinyl, piperazinyl, hexamethyleniminyl, morpholinyl,thiomorpholinyl and the like can be mentioned.

As the “7- to 10-membered crosslinked heterocyclic group”, for example,quinuclidinyl, 7-azabicyclo[2.2.1]heptanyl and the like can bementioned.

The “heterocyclic group” is preferably a 5- to 10-membered (monocyclicor bicyclic) heterocyclic group containing, besides carbon atoms, 1 to 4hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygenatom. As specific examples, an aromatic heterocyclic group such as 2- or3-thienyl; 2-, 3- or 4-pyridyl; 2- or 3-furyl; 2-, 4- or 5-thiazolyl;2-, 4- or 5-oxazolyl; 1-, 3- or 4-pyrazolyl; 2-pyrazinyl; 2-, 4- or5-pyrimidinyl; 1-, 2- or 3-pyrrolyl; 1-, 2- or 4-imidazolyl; 3- or4-pyridazinyl; 3-isothiazolyl; 3-isoxazolyl; 1,2,4-oxadiazol-5-yl;1,2,4-oxadiazol-3-yl; 2-, 3-, 4-, 5- or 8-quinolyl; 1-, 3-, 4-, 5-, 6-,7- or 8-isoquinolyl; 1-, 2- ,3-, 4-, 5-, 6- or 7-indolyl; 1-, 2-, 4- or5-isoindolyl; 1-, 5- or 6-phthalazinyl; 2-, 3- or 5-quinoxalinyl; 2-,3-, 4-, 5- or 6-benzofuranyl; 2-, 3-, 4-, 5- or 6-benzothienyl; 2-, 4-,5- or 6-benzothiazolyl; 1-, 2-, 4-, 5- or 6-benzimidazolyl and the like;

a non-aromatic heterocyclic group such as 1-, 2- or 3-pyrrolidinyl; 1-,2-, 4- or 5-imidazolidinyl; 2- or 4-imidazolinyl; 2-, 3- or4-pyrazolidinyl; piperidino; 2-, 3- or 4-piperidinyl; 1- or2-piperazinyl; morpholino and the like, and the like can be mentioned.

As the “substituent” of the “heterocyclic group optionally havingsubstituent(s)”, those exemplified as the “substituent” of theaforementioned “C₇₋₁₉ aralkyl optionally having substituent(s)” can beused. The number of the substituents is, for example, 1 to 5, preferably1 to 3. When the number of the substituents is not less than 2,respective substituents may be the same or different.

As the “C₁₋₆ alkyl” for R⁴, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and thelike can be mentioned.

As the “nitrogen-containing heterocycle” of the “nitrogen-containingheterocycle optionally having substituent(s)” formed by R³ and R⁴together with the adjacent nitrogen atom, for example, a 3- to10-membered (preferably 3- to 8-membered) nitrogen-containingheterocycle containing at least one nitrogen atom and optionally furthercontaining, besides carbon atoms, 1 to 3 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom, and optionally fusedwith a benzene ring, can be mentioned. As specific examples, aziridine,azetidine, morpholine, thiomorpholine, piperidine, piperazine,pyrrolidine, hexamethylenimine (azepane), heptamethylenimine,hexahydropyrimidine, 1,4-diazepane, thiazolidine, imidazolidine,heptahydroindole, decahydroquinoline, decahydroisoquinoline, and anunsaturated cyclic amine thereof (e.g., 1,2,5,6-tetrahydropyridine,1H-imidazole, 4,5-dihydro-1H-imidazole, 2,3-dihydroindole,1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and thelike) and the like can be mentioned. Of these, piperidine, piperazine,pyrrolidine, hexamethylenimine (azepane), morpholine, thiomorpholine andthe like are preferable.

As the “substituent” of the “nitrogen-containing heterocycle optionallyhaving substituent(s)”, those exemplified as the “substituent” of theaforementioned “C₇₋₁₉ aralkyl optionally having substituent(s)” can beused. The number of the substituents is, for example, 1 to 5, preferably1 to 3. When the number of the substituents is not less than 2,respective substituents may be the same or different. The substituent ispreferably an optionally halogenated C₁₋₁₀ alkyl, an optionallyhalogenated C₁₋₆ alkylsulfonyl and the like.

The “acyl” is preferably a formyl, a carboxy, a carbamoyl, an optionallyhalogenated C₁₋₆ alkyl-carbonyl (e.g., acetyl, propanoyl,2-methylpropanoyl, butanoyl, 3-methylbutanoyl, pentanoyl, hexanoyl andthe like), a C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like), aC₆₋₁₄ aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl and thelike) optionally having substituent(s), a C₆₋₁₄ aryloxy-carbonyl (e.g.,phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and thelike) optionally having substituent(s), a C₇₋₁₉ aralkyloxy-carbonyl(e.g., benzyloxycarbonyl, phenethyloxycarbonyl and the like) optionallyhaving substituent(s), a 5- or 6-membered heterocyclylcarbonyl (e.g.,nicotinoyl, tetrahydrofuroyl and the like) optionally havingsubstituent(s), a mono- or di-C₁₋₆ alkyl-carbamoyl (e.g.,methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl and the like), a C₆₋₁₄ aryl-carbamoyl optionallyhaving substituent(s) (e.g., phenylcarbamoyl, 4-methoxyphenylcarbamoyl,3,4-dimethoxyphenylcarbamoyl and the like), a 5- or 6-memberedheterocyclylcarbamoyl (e.g., pyridylcarbamoyl and the like) optionallyhaving substituent(s), an optionally halogenated C₁₋₆ alkylsulfonyl(e.g., methylsulfonyl, propylsulfonyl, butylsulfonyl and the like), aC₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl and the like) optionally havingsubstituent(s), a C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,cyclohexylcarbonyl and the like) optionally having substituent(s), aC₃₋₆ cycloalkyl-C₁₋₆ alkyl-carbonyl (e.g., cyclopropylmethylcarbonyl,cyclopropylethylcarbonyl, cyclopentylmethylcarbonyl,cyclohexylmethylcarbonyl and the like) optionally having substituent(s)and the like.

Here, as the “optionally halogenated C₁₋₆ alkyl-carbonyl” and“optionally halogenated C₁₋₆ alkylsulfonyl”, those exemplified as the“substituent” of the aforementioned “C₇₋₁₉ aralkyl optionally havingsubstituent(s)” can be used respectively.

As the “C₆₋₁₄ aryl-carbonyl optionally having substituent(s)”, “C₆₋₁₄aryloxy-carbonyl optionally having substituent(s)”, “C₇₋₁₉aralkyloxy-carbonyl optionally having substituent(s)”, “5- or 6-memberedheterocyclylcarbonyl optionally having substituent(s)”, “C₆₋₁₄aryl-carbamoyl optionally having substituent(s)”, “5- or 6-memberedheterocyclylcarbamoyl optionally having substituent(s)” and “C₆₋₁₄arylsulfonyl optionally having substituent(s)”, those exemplified as the“substituent” of the “hydrocarbon group optionally havingsubstituent(s)” for the aforementioned R⁴ can be used respectively.

As the substituent of the “C₃₋₆ cycloalkyl-carbonyl optionally havingsubstituent(s)” and “C₃₋₆ cycloalkyl-C₁₋₆ alkyl-carbonyl optionallyhaving substituent(s)”, those exemplified as the “substituent” of theaforementioned “C₇₋₁₉ aralkyl optionally having substituent(s)” can beused. The number of the substituents is, for example, 1 to 3. When thenumber of the substituents is not less than 2, respective substituentsmay be the same or different.

As the “acylamino” exemplified as the “substituent” for theaforementioned Ar¹, for example, an amino mono- or di-substituted by theaforementioned “acyl” can be mentioned, preferably an acylaminorepresented by formula: —NR⁵—COR⁶, —NR⁵ —COOR⁶, —NR⁵—SO₂R⁶,—NR⁵—CONR⁶R⁷, —NR⁵—PO(—OR⁶)—OR⁷ or —NR⁵—PO₂—R⁶ [wherein R⁵ is a hydrogenatom or a C₁₋₆ alkyl; R⁶ is as defined for the aforementioned R³; and R⁷is as defined for R⁴], and the like can be mentioned.

As the “C₁₋₆ alkyl” for R⁵, those exemplified for the aforementioned R⁴can be mentioned.

The “acylamino” is preferably a formylamino, an optionally halogenatedC₁₋₆ alkyl-carboxamido (e.g., methylcarboxamido,trifluoromethylcarboxamido, propylcarboxamido, isopropylcarboxamido,butylcarboxamido and the like), a C₆₋₁₄ aryl-carboxamido optionallyhaving substituent(s) (e.g., phenylcarboxamido,2-methoxyphenylcarboxamido, 4-methoxyphenylcarboxamido,propanoylmethylphenylcarboxamido and the like), a N-(C₆₋₁₄ aryl-carbonyloptionally having substituent(s))-N-C₁₋₆ alkylamino (e.g.,N-4-methoxybenzoyl-N-methylamino and the like), a C₇₋₁₉aralkyl-carboxamido (e.g., benzylcarboxamido and the like) optionallyhaving substituent(s), an aromatic heterocyclyl-carboxamido (e.g.,benzothiophen-2-ylcarboxamido and the like) optionally havingsubstituent(s), an optionally halogenated C₁₋₆ alkoxy-carboxamido (e.g.,methoxycarboxamido, ethoxycarboxamido, propoxycarboxamido,butoxycarboxamido and the like), a C₆₋₁₄ arylamino-carbonylamino (e.g.,phenylaminocarbonylamino and the like) optionally having substituent(s),an optionally halogenated C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, trifluoromethylsulfonylamino, ethylsulfonylaminoand the like), a C₆₋₁₄ arylsulfonylamino optionally havingsubstituent(s) (e.g., 4-methoxyphenylsulfonylamino and the like) and thelike.

Here, as the “substituent” of the “C₆₋₁₄ aryl-carboxamido optionallyhaving substituent(s)”, “N-(C₆₋₁₄ aryl-carbonyl optionally havingsubstituent(s))-N-C₁₋₆ alkylamino”, “C₇₋₁₉ aralkyl-carboxamidooptionally having substituent(s)”, “aromatic heterocyclyl-carboxamidooptionally having substituent(s)”, “C₆₋₁₄ arylamino-carbonylaminooptionally having substituent(s)” and “C₆₋₁₄ arylsulfonylaminooptionally having substituent(s)”, those exemplified as the“substituent” of the aforementioned “C₇₋₁₉ aralkyl optionally havingsubstituent(s)” can be used. The number of the substituents is, forexample, 1 to 5, preferably 1 to 3. When the number of the substituentsis not less than 2, respective substituents may be the same ordifferent.

As the “acyloxy” exemplified as the “substituent” for the aforementionedAr¹, for example, an oxy mono-substituted by the aforementioned “acyl”can be mentioned, preferably an acyloxy represented by the formula:—O—COR⁸, —O—COOR⁸, —O—CONHR⁸, —O—PO(OH)—OR⁸ or —O—PO₂—R⁸ [wherein R⁸ isas defined for the aforementioned R³], and the like can be mentioned.

The “acyloxy” is preferably an optionally halogenated C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propanoyloxy, butanoyloxy and thelike), a C₆₋₁₄ aryl-carbonyloxy optionally having substituent(s) (e.g.,benzoyloxy, 4-methoxybenzoyloxy and the like), an optionally halogenatedC₁₋₆ alkoxy-carbonyloxy (e.g., methoxycarbonyloxy,trifluoromethoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy and the like), a mono- or di-C₁₋₆ alkyl-carbamoyloxy(e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy and the like), a C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy and the like) optionally havingsubstituent(s), nicotinoyloxy and the like.

As the “substituent” of the “C₆₋₁₄ aryl-carbonyloxy optionally havingsubstituent(s)” and “C₆₋₁₄ aryl-carbamoyloxy optionally havingsubstituent(s)”, those exemplified as the “substituent” of theaforementioned “C₇₋₁₉ aralkyl optionally having substituent(s)” can beused. The number of the substituents is, for example, 1 to 5, preferably1 to 3. When the number of the substituents is not less than 2,respective substituents may be the same or different.

As the “acyl-C₁₋₆ alkyl”, “acylamino-C₁₋₆ alkyl” and “acyloxy-C₁₋₆alkyl” exemplified as the “substituent” for the aforementioned Ar¹, aC₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like) substituted by theaforementioned “acyl”, “acylamino” and “acyloxy” can be mentionedrespectively.

The “substituent” of the “cyclic group optionally having substituent(s)”for Ar¹ is preferably a halogen atom (e.g., fluorine, chlorine, bromine,iodine and the like), a C₁₋₃ alkylenedioxy (e.g., methylenedioxy,ethylenedioxy and the like), a nitro, a cyano, an optionally halogenatedC₁₋₁₀ alkyl, an aromatic group optionally having substituent(s), anon-aromatic group optionally having substituent(s), an optionallyhalogenated C₁₋₁₀ alkoxy, a C₆₋₁₄ aryloxy optionally havingsubstituent(s), a C₇₋₁₉ aralkyloxy optionally having substituent(s), aC₃₋₆ cycloalkyl-C₁₋₆ alkyl optionally having substituent(s), a C₃₋₆cycloalkyl-C₁₋₆ alkoxy optionally having substituent(s), an acyl, anacyl-C₁₋₆ alkyl, a hydroxy, a C₁₋₆ alkoxy-C₁₋₆ alkoxy, an optionallyhalogenated C₁₋₁₀ alkylthio, an acylamino, an acyloxy, an acyl-C₁₋₆alkyl and the like.

Ar¹ is preferably a group represented by the formula: Ar³—Ar²— (whereinAr² is a cyclic group optionally having substituent(s) and Ar³ is anaromatic group optionally having substituent(s)).

Here, as the “cyclic group” of the “cyclic group optionally havingsubstituent(s)” for Ar², the “aromatic group”, “non-aromatic cyclichydrocarbon group” and “non-aromatic heterocyclic group” exemplified forthe aforementioned Ar¹ can be mentioned. The “cyclic group” ispreferably phenyl, a 5- or 6-membered aromatic heterocyclic group, a 5-to 8-membered monocyclic non-aromatic heterocyclic group and the like,more preferably phenyl, pyridyl, piperidinyl and the like.

As the “substituent” of the “cyclic group optionally havingsubstituent(s)” for Ar², those exemplified as the substituent for theaforementioned Ar¹ can be used. The number of the substituents is, forexample, 1 to 4, preferably 1 to 3. When the number of the substituentsis not less than 2, respective substituents may be the same ordifferent. The substituent is preferably a halogen atom (preferablyfluorine, chlorine and the like), an optionally halogenated C₁₋₆ alkyl(preferably methyl, trifluoromethyl, ethyl and the like) and the like.

As the “aromatic group optionally having substituent(s)” for Ar³, thoseexemplified as the “substituent” of the “cyclic group optionally havingsubstituent(s)” for the aforementioned Ar¹ can be mentioned. The“aromatic group” is preferably phenyl, naphthyl, a 5- or 6-memberedaromatic heterocyclic group, a 9- to 10-membered fused polycyclicaromatic heterocyclic group and the like, more preferably phenyl, a 5-or 6-membered aromatic heterocyclic group and the like. Of these,phenyl, pyridyl and the like are preferable.

The “aromatic group” optionally has, for example, 1 to 4, preferably 1to 3, substituents at substitutable positions. As such substituents,those exemplified as the “substituent” of the aforementioned “C₇₋₁₉aralkyl optionally having substituent(s)” can be mentioned. Of these, ahalogen atom (preferably fluorine, chlorine and the like), an optionallyhalogenated C₁₋₆ alkyl (preferably methyl, trifluoromethyl, ethyl andthe like), an optionally halogenated C₁₋₆ alkoxy (preferably methoxy,trifluoromethoxy and the like), an optionally halogenated C₁₋₆ alkylthio(preferably methylthio and the like), a C₁₋₃ alkylenedioxy (preferablymethylenedioxy, ethylenedioxy and the like), an optionally halogenatedC₁₋₆ alkyl-carbonyl (preferably acetyl and the like), an optionallyhalogenated C₁₋₆ alkyl-carboxamido (preferably isopropylcarboxamido andthe like) and the like are preferable.

As specific examples of the aforementioned group represented by theformula: Ar³Ar²— (the symbols in the formula are as defined above), 2-,3- or 4-biphenylyl; 3-(1-naphthyl)-1,2,4-oxadiazol-5-yl;3-(2-naphthyl)-1,2,4-oxadiazol-5-yl;3-(2-benzofuranyl)-1,2,4-oxadiazol-5-yl; 3-phenyl-1,2,4-oxadiazol-5-yl;3-(2-benzoxazolyl)-1,2,4-oxadiazol-5-yl;3-(3-indolyl)-1,2,4-oxadiazol-5-yl; 3-(2-indolyl)-1,2,4-oxadiazol-5-yl;4-phenylthiazol-2-yl; 4-(2-benzofuranyl)thiazol-2-yl;4-phenyl-1,3-oxazol-5-yl; 5-phenyl-isothiazol-4-yl; 5-phenyloxazol-2-yl;4-(2-thienyl)phenyl; 4-(3-thienyl)phenyl; 3-(3-pyridyl)phenyl;4-(3-pyridyl)phenyl; 6-phenyl-3-pyridyl; 5-phenyl-1,3,4-oxadiazol-2-yl;4-(2-naphthyl)phenyl; 4-(2-benzofuranyl)phenyl; 4,4′-terphenyl;5-phenyl-2-pyridyl; 2-phenyl-5-pyrimidinyl; 4-(4-pyridyl)phenyl;2-phenyl-1,3-oxazol-5-yl; 2,4-diphenyl-1,3-oxazol-5-yl;3-phenyl-isoxazol-5-yl; 5-phenyl-2-furyl; 4-(2-furyl)phenyl;4-(3-furyl)phenyl; 4-(2-benzothienyl)phenyl; 4-phenyl-1-pyrrolidinyl;4-phenyl-1-piperidinyl and the like, each of which optionally has 1 to 3substituents, can be mentioned. Of these, 2-, 3- or 4-biphenylyl;4-(2-thienyl)phenyl; 4-(3-thienyl)phenyl; 4-(2-furyl)phenyl;4-(3-furyl)phenyl; 6-phenyl-3-pyridyl; 5-phenyl-2-pyridyl;4-(2-naphthyl)phenyl; 4-(2-benzofuranyl)phenyl;4-(2-benzothienyl)phenyl; 4-phenyl-1-piperidinyl and the like arepreferable.

Here, as preferable examples of the substituent, a halogen atom(preferably fluorine, chlorine and the like), an optionally halogenatedC₁₋₆ alkyl (preferably methyl, trifluoromethyl, ethyl and the like), anoptionally halogenated C₁₋₆ alkoxy (preferably methoxy, trifluoromethoxyand the like), an optionally halogenated C₁₋₆ alkylthio (preferablymethylthio and the like), a C₁₋₃ alkylenedioxy (preferablymethylenedioxy, ethylenedioxy and the like), an optionally halogenatedC₁₋₆ alkyl-carbonyl (preferably acetyl and the like), an optionallyhalogenated C₁₋₆ alkyl-carboxamido (preferably isopropylcarboxamido andthe like) and the like can be mentioned.

As preferable examples of Ar¹, phenyl, a 5- or 6-membered aromaticheterocyclic group or a 5- to 8-membered monocyclic non-aromaticheterocyclic group (preferably phenyl, pyridyl, piperidinyl), eachoptionally having 1 to 3 substituents selected from a halogen atom(e.g., fluorine, chlorine, bromine, iodine and the like), a C₁₋₃alkylenedioxy (e.g., methylenedioxy, ethylenedioxy and the like), anitro, a cyano, an optionally halogenated C₁₋₁₀ alkyl (e.g., methyl,ethyl, propyl, butyl, pentyl), an optionally halogenated C₁₋₁₀ alkoxy(e.g., methoxy, ethoxy, propoxy, butoxy, isobutoxy, pentyloxy,isopentyloxy and the like), a C₆₋₁₄ aryloxy (preferably phenoxy)optionally having substituent(s) (preferably a halogen atom, anoptionally halogenated C₁₋₁₀ alkyl, an optionally halogenated C₁₋₁₀alkoxy and the like), a C₇₋₁₉ aralkyloxy (preferably benzyloxy)optionally having substituent(s) (preferably a halogen atom, anoptionally halogenated C₁₋₁₀ alkyl, an optionally halogenated C₁₋₁₀alkoxy and the like), a C₃₋₆ cycloalkyl-C₁₋₆ alkyl (preferablycyclopropylmethyl) optionally having substituent(s) (preferably ahalogen atom, an optionally halogenated C₁₋₁₀ alkyl, an optionallyhalogenated C₁₋₁₀ alkoxy and the like), a C₃₋₆ cycloalkyl-C₁₋₆ alkoxy(preferably cyclopropylmethoxy, cyclopropylethoxy) optionally havingsubstituent(s) (preferably a halogen atom, an optionally halogenatedC₁₋₁₀ alkyl, an optionally halogenated C₁₋₁₀ alkoxy and the like), anacyl [preferably an optionally halogenated C₁₋₆ alkyl-carbonyl (e.g.,pentanoyl, hexanoyl and the like), an optionally halogenated C₁₋₆alkylsulfonyl (e.g., butylsulfonyl and the like) and the like], anacyl-C₁₋₆ alkyl [preferably an optionally halogenated C₁₋₆alkyl-carbonyl-C₁₋₆ alkyl (e.g., propanoylmethyl, propanoylethyl,2-methylpropanoylmethyl, butanoylmethyl, 3-methylbutanoylmethyl,pentanoylmethyl and the like), an optionally halogenated C₁₋₆alkylsulfonyl-C₁₋₆ alkyl (e.g., propylsulfonylmethyl,butylsulfonylmethyl and the like), a C₆₋₁₄ aryl-carbonyl-C₁₋₆ alkyl(e.g., benzoylmethyl and the like), a C₃₋₆ cycloalkyl-carbonyl-C₁₋₆alkyl (e.g., cyclopropylcarbonylmethyl, cyclobutylcarbonylmethyl and thelike), a 5- or 6-membered heterocyclylcarbonyl-C₁₋₆ alkyl (e.g.,tetrahydrofuroylmethyl and the like) and the like], a hydroxy, a C₁₋₆alkoxy-C₁₋₆ alkoxy (preferably methoxymethoxy, ethoxyethoxy), anoptionally halogenated C₁₋₁₀ alkylthio (preferably methylthio, butylthioand the like), an acylamino [preferably an optionally halogenated C₁₋₆alkyl-carboxamido (e.g., propylcarboxamido, isopropylcarboxamido,butylcarboxamido and the like), a C₆₋₁₄ aryl-carboxamido optionallyhaving substituent(s) (preferably a C₁₋₆ alkyl-carbonyl-C₁₋₆ alkyl)(preferably phenylcarboxamido, propanoylmethylphenylcarboxamido and thelike) and the like], an acyloxy [preferably a C₁₋₆ alkyl-carbonyloxy(e.g., propanoyloxy, butanoyloxy and the like)] and the like, can bealso mentioned.

Of the above-mentioned substituents, a halogen atom, a C₁₋₃alkylenedioxy, a nitro, a cyano, an optionally halogenated C₁₋₁₀ alkyl,an optionally halogenated C₁₋₁₀ alkoxy, a C₆₋₁₄ aryloxy optionallyhaving substituent(s), a C₇₋₁₉ aralkyloxy optionally havingsubstituent(s), a C₃₋₆ cycloalkyl-C₁₋₆ alkoxy optionally havingsubstituent(s), an acyl, an acyl-C₁₋₆ alkyl and the like are preferable.

As the “alkylene group” of the “optionally halogenated alkylene group”for Y, for example, a C₁₋₆ alkylene group [for example, —CH₂—, —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CH(CH₃)—, —CH(C₂H₅)—,—CH(CH(CH₃)₂)—, —C(CH₃)₂—, —(CH(CH₃))₂—, —(CH₂)₂C(CH₃)₂— and—(CH₂)₃C(CH₃)₂—] and the like can be mentioned.

The alkylene group is optionally substituted by 1 to 5, preferably 1 to3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine). Thehalogen atom is preferably fluorine. When the alkylene group issubstituted by two or more halogen atoms, the kinds of the halogen atomsmay be the same or different.

Y is preferably a C₁₋₆ alkylene group, more preferably —CH₂—, —CH(CH₃)—,—CH(C₂H₅)—, —CH(CH(CH₃)₂)— and the like.

As the “optionally halogenated C₁₋₆ alkyl” for R, of the “optionallyhalogenated C₁₋₁₀ alkyl” exemplified as the “substituent” of the “cyclicgroup optionally having substituent(s)” for the aforementioned Ar¹,those having 1 to 6 carbon atoms can be used. The “optionallyhalogenated C₁₋₆ alkyl” is preferably a C₁₋₆ alkyl, particularly,methyl, ethyl, propyl, isopropyl and the like are preferable.

As the “substituent” of the “phenyl optionally having substituent(s)”and “pyridyl optionally having substituent(s)” for R, for example, ahalogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), aC₁₋₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy and the like), anitro, a cyano, an optionally halogenated C₁₋₁₀ alkyl, an optionallyhalogenated C₃₋₆ cycloalkyl, an optionally halogenated C₁₋₁₀ alkoxy, anoptionally halogenated C₁₋₁₀ alkylthio, a hydroxy, an amino, a mono- ordi-C₁₋₁₀ alkylamino (e.g., methylamino, ethylamino, propylamino,isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino,dibutylamino, ethylmethylamino and the like), a formyl, a carboxy, acarbamoyl, a thiocarbamoyl, an optionally halogenated C₁₋₆alkyl-carbonyl, a C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like), amono- or di-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like),an optionally halogenated C₁₋₆ alkylsulfonyl, a formylamino, anoptionally halogenated C₁₋₆ alkyl-carboxamido, a C₁₋₆ alkoxy-carboxamido(e.g., methoxycarboxamido, ethoxycarboxamido, propoxycarboxamido,butoxycarboxamido and the like), a C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino and the like), a C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propanoyloxy and the like), a C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy and the like), a mono- or di-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy,dimethylcarbamoyloxy, diethylcarbamoyloxy and the like), an aromaticgroup optionally having substituent(s) and the like can be mentioned.The number of the substituents is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is not less than 2, respectivesubstituents may be the same or different.

Here, as the “optionally halogenated C₁₋₁₀ alkyl”, “optionallyhalogenated C₁₋₁₀ alkoxy” and “optionally halogenated C₁₋₁₀ alkylthio”,those exemplified as the “substituent” of the “cyclic group optionallyhaving substituent(s)” for the aforementioned Ar¹ can be used.

As the “optionally halogenated C₁₋₆ alkyl-carbonyl”, “optionallyhalogenated C₁₋₆ alkylsulfonyl” and “optionally halogenated C₁₋₆alkyl-carboxamido”, those exemplified as the “substituent” of theaforementioned “C₇₋₁₉ aralkyl optionally having substituent(s)” can beused.

As the “aromatic group optionally having substituent(s)”, thoseexemplified as the substituent of the “cyclic group optionally havingsubstituent(s)” for the aforementioned Ar¹ can be used.

R is preferably a hydrogen atom.

As the “optionally halogenated C₁₋₆ alkyl”, “optionally halogenated C₁₋₆alkoxy” and “optionally halogenated C₁₋₆ alkylthio” for Ra¹, Ra², Ra³ orRa⁴, of the “optionally halogenated C₁₋₁₀ alkyl”, “optionallyhalogenated C₁₋₁₀ alkoxy” and “optionally halogenated C₁₋₁₀ alkylthio”exemplified as the “substituent” of the “cyclic group optionally havingsubstituent(s)” for the aforementioned Ar¹, those having 1 to 6 carbonatoms can be used respectively.

As the “optionally halogenated C₁₋₆ alkyl-carbonyl” and “optionallyhalogenated C₁₋₆ alkylsulfonyl” for Ra¹, Ra², Ra³ or Ra⁴, thoseexemplified as the “substituent” of the aforementioned “C₇₋₁₉ aralkyloptionally having substituent(s)” can be used respectively.

As the “substituent” of the “phenyl optionally having substituent(s)”and “pyridyl optionally having substituent(s)” for Ra¹, Ra², Ra³ or Ra⁴,those exemplified for the aforementioned R can be used.

As the “halogen atom” for Ra¹, Ra², Ra³ or Ra⁴, for example, fluorine,chlorine, bromine and iodine can be mentioned respectively.

As the “mono- or di-C₁₋₆ alkylamino” for Ra¹, Ra², Ra³ or Ra⁴, forexample, an amino mono- or di-substituted by C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl) can be mentioned. To be specific,methylamino, ethylamino, propylamino, isopropylamino, butylamino,dimethylamino, diethylamino, dipropylamino, dibutylamino,ethylmethylamino and the like can be mentioned.

Ra¹, Ra², Ra³ and Ra⁴ are the same or different and each is preferably ahydrogen atom or an optionally halogenated C₁₋₆ alkyl. Ra¹, Ra², Ra³ andRa⁴ are each more preferably a hydrogen atom.

As the “monocyclic aromatic ring” of the “monocyclic aromatic ringoptionally having substituent(s)” for Ar, benzene and a 5- or 6-memberedaromatic heterocycle can be mentioned.

As the “5- or 6-membered aromatic heterocycle”, for example, a 5- or6-membered aromatic heterocycle containing, besides carbon atoms, one ormore (e.g., 1 to 3) hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom, can be mentioned. To be specific, thiophene,furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole,isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, oxadiazole,thiadiazole, furazan and the like can be mentioned.

The “monocyclic aromatic ring” is preferably a benzene ring, a pyridinering, a furan ring or a thiophene ring, more preferably a benzene ring.

When the “monocyclic aromatic ring” for Ar is a benzene ring, a pyridinering, a furan ring or a thiophene ring, substitutable positions of agroup represented by the formula

wherein the symbols in the formula are as defined above, and a grouprepresented by the formula

wherein the symbols in the formula are as defined above, are preferably1,4-positions on benzene ring; 2,5-positions on pyridine ring;2,5-positions or 2,4-positions on furan ring; or 2,5-positions or2,4-positions on thiophene ring, represented by the formula

The “monocyclic aromatic ring” for Ar optionally further hassubstituent(s), besides a group represented by the formula

wherein the symbols in the formula are as defined above, and a grouprepresented by the formula

wherein the symbols in the formula are as defined above. As such“substituent”, those similar to the “substituent” of the aforementioned“C₇₋₁₉ aralkyl optionally having substituent(s)” can be used.

The number of the substituents is 1 to 4, preferably 1 or 2. When thenumber of the substituents is not less than 2, respective substituentsmay be the same or different.

The substituent is preferably a halogen atom (preferably fluorine,chlorine, bromine and the like), an optionally halogenated C₁₋₁₀ alkyl(preferably methyl, ethyl, propyl, trifluoromethyl and the like), anoptionally halogenated C₁₋₁₀ alkoxy (preferably methoxy, ethoxy and thelike), an optionally halogenated C₁₋₁₀ alkylthio (preferably methylthioand the like), a hydroxy, an amino, a mono- or di-C₁₋₁₀ alkylamino(preferably methylamino, dimethylamino and the like), a formyl, acarboxy, a C₁₋₆ alkoxy-carbonyl (preferably methoxycarbonyl,ethoxycarbonyl and the like), an optionally halogenated C₁₋₆alkyl-carboxamido (preferably methylcarboxamido,trifluoromethylcarboxamido and the like), a 5- or 6-memberednon-aromatic heterocyclic group (preferably pyrrolidinyl and the like)and the like, more preferably a halogen atom (preferably fluorine,chlorine, bromine and the like), an optionally halogenated C₁₋₆ alkyl(preferably methyl, ethyl, propyl, trifluoromethyl and the like), anoptionally halogenated C₁₋₆ alkoxy (preferably methoxy, ethoxy and thelike) and the like.

Ar is preferably an unsubstituted benzene ring.

As the “C₁₋₆ alkyl” for R¹ or R², those exemplified for theaforementioned R⁵ can be used. Of those, methyl, ethyl, propyl andisopropyl are preferable.

As the “nitrogen-containing heterocycle” of the “nitrogen-containingheterocycle optionally having substituent(s)” formed by R¹ and R²together with the adjacent nitrogen atom, those exemplified as the“nitrogen-containing heterocycle” of the “nitrogen-containingheterocycle optionally having substituent(s)” formed by theaforementioned R³ and R⁴ together with the adjacent nitrogen atom can beused. Of those, azetidine, morpholine, thiomorpholine, piperidine,piperazine, pyrrolidine, hexamethylenimine (azepane), 1,3-thiazolidine,1H-imidazole, 4,5-dihydro-1H-imidazole, 2,3-dihydroindole,1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and the likeare preferable, and piperidine, piperazine, pyrrolidine,hexamethylenimine (azepane), morpholine, thiomorpholine and the like aremore preferable. Particularly, piperidine, pyrrolidine,hexamethylenimine, morpholine and thiomorpholine are preferable.

As the “substituent” of the “nitrogen-containing heterocycle optionallyhaving substituent(s)”, for example, “C₇₋₁₉ aralkyl optionally havingsubstituent(s)” and “aromatic group optionally having substituent(s)”exemplified as the “substituent” of the “cyclic group optionally havingsubstituent(s)” for Ar¹ can be used in addition to the “substituent”exemplified for the aforementioned “C₇₋₁₉ aralkyl optionally havingsubstituent(s)”. The number of the substituents is, for example, 1 to 5,preferably 1 to 3. When the number of the substituents is not less than2, the respective substituents may be the same or different.

The substituent is preferably an optionally halogenated C₁₋₁₀ alkyl(preferably methyl, ethyl, propyl, butyl, isobutyl and the like); anoptionally halogenated C₃₋₆ cycloalkyl (preferably cyclohexyl and thelike); a carbamoyl; a mono- or di-C₁₋₆ alkyl-carbamoyl (preferablymethylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl andthe like); a 5- or 6-membered heterocyclylcarbonyl (preferablymorpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl and thelike); an optionally halogenated C₁₋₆ alkylsulfonyl (preferablymethylsulfonyl and the like); an optionally halogenated C₁₋₆alkyl-carboxamido (preferably acetamido and the like); a hydroxy-C₁₋₆alkyl (preferably hydroxymethyl, hydroxyethyl and the like); acarbamoyl-C₁₋₆ alkyl (preferably carbamoylmethyl, carbamoylethyl,carbamoylpropyl and the like); a mono- or di-C₁₋₆ alkyl-carbamoyl-C₁₋₆alkyl (preferably methylcarbamoylmethyl, methylcarbamoylethyl,methylcarbamoylpropyl, dimethylcarbamoylmethyl, dimethylcarbamoylethyl,dimethylcarbamoylpropyl, ethylcarbamoylmethyl, ethylcarbamoylethyl,ethylcarbamoylpropyl, diethylcarbamoylmethyl, diethylcarbamoylethyl,diethylcarbamoylpropyl and the like); a 5- or 6-memberedheterocyclylcarbonyl-C₁₋₆ alkyl (preferably morpholinocarbonylmethyl,morpholinocarbonylethyl, morpholinocarbonylpropyl,piperidinocarbonylmethyl, piperidinocarbonylethyl,piperidinocarbonylpropyl, 1-pyrrolidinylcarbonylmethyl,1-pyrrolidinylcarbonylethyl, 1-pyrrolidinylcarbonylpropyl and the like);a mono- or di-C₁₋₆ alkyl-carbamoyl-C₁₋₆ alkoxy (preferablyethylcarbamoylmethoxy and the like); a C₇₋₁₉ aralkyl (preferably benzyland the like) optionally having substituent(s); an aromatic group(preferably phenyl and the like) optionally having substituent(s) andthe like.

As the substituent of the “C₇₋₁₉ aralkyl optionally havingsubstituent(s)” and “aromatic group optionally having substituent(s)”, ahalogen atom (preferably fluorine, chlorine and the like), an optionallyhalogenated C₁₋₆ alkyl (preferably methyl and the like), an optionallyhalogenated C₁₋₆ alkoxy (preferably methoxy and the like) and the likeare preferable. The number of the substituents is, for example, 1 to 3,preferably 1 or 2. When the number of the substituents is not less than2, the respective substituents may be the same or different.

In addition, the above-mentioned “5- or 6-membered heterocyclylcarbonyl”and “5- or 6-membered heterocyclylcarbonyl-C₁₋₆ alkyl” optionally have 1to 3 substituents selected from a halogen atom (preferably fluorine,chlorine and the like), an optionally halogenated C₁₋₆ alkyl (preferablymethyl and the like), an optionally halogenated C₁₋₆ alkoxy (preferablymethoxy and the like) and the like.

The “substituent” of the “nitrogen-containing heterocycle optionallyhaving substituent(s)” is more preferably an optionally halogenatedC₁₋₁₀ alkyl, an optionally halogenated C₁₋₆ alkylsulfonyl and the like.

As the “nitrogen-containing heterocycle optionally havingsubstituent(s)” formed by R¹ and Y together with the adjacent nitrogenatom, those exemplified as the “nitrogen-containing heterocycleoptionally having substituent(s)” formed by the aforementioned R¹ and R²together with the adjacent nitrogen atom can be used.

Of compound (I), a compound wherein R¹ and R² are the same or differentand each is a hydrogen atom or a C₁₋₆ alkyl, or R¹ and R² form anitrogen-containing heterocycle optionally having substituent(s)together with the adjacent nitrogen atom is preferable, a compoundwherein R¹ and R² form a nitrogen-containing heterocycle optionallyhaving substituent(s) together with the adjacent nitrogen atom is morepreferable.

In compound (I), when the nitrogen-containing heterocycle formed by R¹and R² together with the adjacent nitrogen atom is piperazine, or when Ris a C₁₋₄ alkyl, then Ar¹ is a cyclic group having substituent(s)

As preferable examples of compound (I), the following compounds can bementioned.

1) A compound wherein

-   Ar¹ is a group represented by the formula: Ar³—Ar²—, wherein    -   Ar² is a phenyl, a 5- or 6-membered aromatic heterocyclic group        or a 5- to 8-membered monocyclic non-aromatic heterocyclic group        (preferably phenyl, pyridyl, piperidinyl), each optionally        having 1 to 3 substituents selected from a halogen atom        (preferably fluorine, chlorine and the like) and an optionally        halogenated C₁₋₆ alkyl (preferably methyl, trifluoromethyl,        ethyl and the like), and    -   Ar³ is a phenyl or a 5- or 6-membered aromatic heterocyclic        group (preferably phenyl, pyridyl and the like), each optionally        having 1 to 3 substituents selected from a halogen atom        (preferably fluorine, chlorine and the like), an optionally        halogenated C₁₋₆ alkyl (preferably methyl, trifluoromethyl,        ethyl and the like), an optionally halogenated C₁₋₆ alkoxy        (preferably methoxy, trifluoromethoxy and the like), an        optionally halogenated C₁₋₆ alkylthio (preferably methylthio and        the like), a C₁₋₃ alkylenedioxy (preferably methylenedioxy,        ethylenedioxy and the like), an optionally halogenated C₁₋₆        alkyl-carbonyl (preferably acetyl and the like) and an        optionally halogenated C₁₋₆ alkyl-carboxamido (preferably        isopropylcarboxamido and the like);-   Ra¹, Ra², Ra³ and Ra⁴ are the same or different and each is a    hydrogen atom or an optionally halogenated C₁₋₆ alkyl;-   R¹ and R² are the same or different and each is a hydrogen atom or a    C₁₋₆ alkyl (preferably methyl, ethyl, propyl, isopropyl);-   Y is a C₁₋₆ alkylene group (preferably —CH₂—, —CH(CH₃)—, —CH(C₂H₅)—,    —CH(CH(CH₃)₂)—);-   R is a hydrogen atom; and-   Ar is a monocyclic aromatic ring (preferably a benzene ring, a    pyridine ring) optionally further having 1 to 3 substituents    selected from a halogen atom (preferably fluorine, chlorine, bromine    and the like), an optionally halogenated C₁₋₆ alkyl (preferably    methyl, ethyl, propyl, trifluoromethyl and the like) and an    optionally halogenated C₁₋₆ alkoxy (preferably methoxy, ethoxy and    the like).    2) A compound wherein-   Ar¹ is a group represented by the formula: Ar³—Ar²—, wherein    -   Ar² is a phenyl, a 5- or 6-membered aromatic heterocyclic group        or a 5- to 8-membered monocyclic non-aromatic heterocyclic group        (preferably phenyl, pyridyl, piperidinyl), each optionally        having 1 to 3 substituents selected from a halogen atom        (preferably fluorine, chlorine and the like) and an optionally        halogenated C₁₋₆ alkyl (preferably methyl, trifluoromethyl,        ethyl and the like), or    -   Ar³ is a phenyl or a 5- or 6-membered aromatic heterocyclic        group (preferably phenyl, pyridyl and the like), each optionally        having 1 to 3 substituents selected from a halogen atom        (preferably fluorine, chlorine and the like), an optionally        halogenated C₁₋₆ alkyl (preferably methyl, trifluoromethyl,        ethyl and the like), an optionally halogenated C₁₋₆ alkoxy        (preferably methoxy, trifluoromethoxy and the like), an        optionally halogenated C₁₋₆ alkylthio (preferably methylthio and        the like), a C₁₋₃ alkylenedioxy (preferably methylenedioxy,        ethylenedioxy and the like), an optionally halogenated C₁₋₆        alkyl-carbonyl (preferably acetyl and the like) and an        optionally halogenated C₁₋₆ alkyl-carboxamido (preferably        isopropylcarboxamido and the like);-   Ra¹, Ra², Ra³ and Ra⁴ are the same or different and each is a    hydrogen atom or an optionally halogenated C₁₋₆ alkyl;-   R¹ and R² form, together with the adjacent nitrogen atom, a 3- to    8-membered nitrogen-containing heterocycle (preferably piperidine,    piperazine, pyrrolidine, hexamethylenimine (azepane), morpholine,    thiomorpholine), each optionally having 1 to 3 substituents selected    from an optionally halogenated C₁₋₁₀ alkyl (preferably methyl,    ethyl, propyl, butyl, isobutyl and the like) and an optionally    halogenated C₁₋₆ alkylsulfonyl (preferably methylsulfonyl and the    like);-   Y is a C₁₋₆ alkylene group (preferably —CH₂—, —CH(CH₃)—, —CH(C₂H₅)—,    —CH(CH(CH₃)₂)—);-   R is a hydrogen atom; and-   Ar is a monocyclic aromatic ring (preferably a benzene ring, a    pyridine ring) optionally further having 1 to 3 substituents    selected from a halogen atom (preferably fluorine, chlorine, bromine    and the like), an optionally halogenated C₁₋₆ alkyl (preferably    methyl, ethyl, propyl, trifluoromethyl and the like) and an    optionally halogenated C₁₋₆ alkoxy (preferably methoxy, ethoxy and    the like).    3) A compound wherein-   Ar¹ is a phenyl, a 5- or 6-membered aromatic heterocyclic group or a    5- to 8-membered monocyclic non-aromatic heterocyclic group    (preferably phenyl, pyridyl, piperidinyl), each optionally having 1    to 3 substituents selected from a halogen atom (e.g., fluorine,    chlorine, bromine, iodine and the like), a C₁₋₃ alkylenedioxy (e.g.,    methylenedioxy, ethylenedioxy and the like), a nitro, a cyano, an    optionally halogenated C₁₋₁₀ alkyl, an optionally halogenated C₁₋₁₀    alkoxy, a C₆₋₁₄ aryloxy (preferably phenoxy) optionally having    substituent(s) (preferably a halogen atom, an optionally halogenated    C₁₋₁₀ alkyl, an optionally halogenated C₁₋₁₀ alkoxy and the like), a    C₇₋₁₉ aralkyloxy (preferably benzyloxy) optionally having    substituent(s) (preferably a halogen atom, an optionally halogenated    C₁₋₁₀ alkyl, an optionally halogenated C₁₋₁₀ alkoxy and the like), a    C₃₋₆ cycloalkyl-C₁₋₆ alkoxy (preferably cyclopropylmethoxy,    cyclopropylethoxy and the like) optionally having substituent(s)    (preferably a halogen atom, an optionally halogenated C₁₋₁₀ alkyl,    an optionally halogenated C₁₋₁₀ alkoxy and the like), an acyl    [preferably an optionally halogenated C₁₋₆ alkyl-carbonyl (e.g.,    pentanoyl, hexanoyl and the like), an optionally halogenated C₁₋₆    alkylsulfonyl (e.g., butylsulfonyl and the like) and the like], an    acyl-C₁₋₆ alkyl [preferably an optionally halogenated C₁₋₆    alkyl-carbonyl-C₁₋₆ alkyl (e.g., propanoylmethyl, propanoylethyl,    2-methylpropanoylmethyl, butanoylmethyl, 3-methylbutanoylmethyl,    pentanoylmethyl and the like), an optionally halogenated C₁₋₆    alkylsulfonyl-C₁₋₆ alkyl (e.g., propylsulfonylmethyl,    butylsulfonylmethyl and the like), a C₆₋₁₄ aryl-carbonyl-C₁₋₆ alkyl    (e.g., benzoylmethyl and the like), a C₃₋₆ cycloalkyl-carbonyl-C₁₋₆    alkyl (e.g., cyclopropylcarbonylmethyl, cyclobutylcarbonylmethyl and    the like), a 5- or 6-membered heterocyclylcarbonyl-C₁₋₆ alkyl (e.g.,    tetrahydrofuroylmethyl and the like) and the like] and the like;-   Ra¹, Ra², Ra³ and Ra⁴ are the same or different and each is a    hydrogen atom or an optionally halogenated C₁₋₆ alkyl;-   R¹ and R² form, together with the adjacent nitrogen atom, a 3- to    8-membered nitrogen-containing heterocycle (preferably piperidine,    piperazine, pyrrolidine, hexamethylenimine (azepane), morpholine,    thiomorpholine), each optionally having 1 to 3 substituents selected    from an optionally halogenated C₁₋₁₀ alkyl (preferably methyl,    ethyl, propyl, butyl, isobutyl and the like) and an optionally    halogenated C₁₋₆ alkylsulfonyl (preferably methylsulfonyl and the    like);-   Y is a C₁₋₆ alkylene group (preferably —CH₂—, —CH(CH₃)—, —CH(C₂H₅)—,    —CH(CH(CH₃)₂)—);-   R is a hydrogen atom; and-   Ar is a monocyclic aromatic ring (preferably a benzene ring, a    pyridine ring) optionally further having 1 to 3 substituents    selected from a halogen atom (preferably fluorine, chlorine, bromine    and the like), an optionally halogenated C₁₋₆ alkyl (preferably    methyl, ethyl, propyl, trifluoromethyl and the like) and an    optionally halogenated C₁₋₆ alkoxy (preferably methoxy, ethoxy and    the like).    4)-   4′-chloro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide    (Example 2);-   4′-chloro-3-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide    (Example 7);-   4′-chloro-N-(2-{4-[1-(1-pyrrolidinyl)propyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide    (Example 33);-   4-(cyclopropylmethoxy)-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide    (Example 40);-   4′-methoxy-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide    (Example 97);-   N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(cyclopropylmethoxy)benzamide    (Example 127);-   N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(2-cyclopropylethoxy)benzamide    (Example 128);-   4′-chloro-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide    (Example 137); or-   4-(2-cyclopropylethoxy)-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide    (Example 148).

When the compound (I) is in the form of a salt, concrete examplesthereof include salts with inorganic bases, ammonium salts, salts withorganic bases, salts with inorganic acids, salts with organic acids,salts with basic or acidic amino acids and the like.

Preferable examples of the salts with inorganic bases include alkalimetal salts such as sodium salt, potassium salt, and the like; alkalineearth metal salts such as calcium salts, magnesium salts, barium salts,and the like; aluminum salts, and the like.

Preferable examples of the salts with organic bases include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine, and the like.

Preferable examples of the salts with inorganic acids include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, and the like.

Preferable examples of the salts with organic acids include salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, and the like.

Preferable examples of the salts with basic amino acids include saltswith arginine, lysine, ornithine, and the like.

Preferable examples of the salts with acidic amino acids include saltswith aspartic acid, glutamic acid, and the like.

Of these, pharmaceutically acceptable salts are preferable. Preferableexamples when compound (I) has an acidic functional group includeinorganic salts such as alkali metal salts (e.g., sodium salt, potassiumsalt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesiumsalt, barium salt, etc.) and the like, ammonium salts, etc.; and whencompound (I) has a basic functional group, inorganic salts such ashydrochloride, sulfate, phosphate and hydrobromide; or organic saltssuch as acetate, maleate, fumarate, succinate, methanesulfonate,p-toluenesulfonate, citrate and tartrate.

The compound (I) may be an anhydrate or a hydrate. When it is a hydrate,it may contain 0.5 to 3 water molecules.

Furthermore, compound (I) may be labeled with an isotope (e.g., ³H, ¹⁴C,³⁵S, etc.).

Where compound (I) includes optical isomers, stereo isomers, regioisomers and rotational isomers, these are within the scope of compound(I), and can be isolated as their single compound through synthesis orseparation known per se. For example, where optical isomers of compound(I) exist, those resolved from their mixtures through optical resolutionare within the scope of compound (I).

Said optical isomers can be produced by methods known per se.Concretely, optically active synthetic intermediates may be used, ormixtures of racemate of the final product are subjected to ordinaryoptical resolution to give the corresponding optical isomers.

As the optical resolution method, methods known per se such asfractional recrystallization method, chiral column method, diastereomermethod which are described in detail below and the like are employed.

1) Fractional Recrystallization Method

The method which comprises allowing a racemate to react with anoptically active compound (e.g., (+)-mandelic acid, (−)-mandelic acid,(+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine,(−)-1-phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.) togive a salt, which is then isolated through fractional recrystallizationmethod, followed by, when desired, subjecting the isolated compound toneutralization to obtain free optical isomers.

2) Chiral Column Method

The method of separating a racemate or a salt thereof, which comprisesutilizing a column for fractionating optical isomers (chiral column). Inthe case of liquid chromatography, for example, a mixture of opticalisomers is applied to a chiral column, such as ENANTIO-OVM (manufacturedby Tosoh Corp.), CHIRAL SERIES (manufactured by Daicel Co.), and thelike, which is then eluted with water, various buffers (e.g., phosphatebuffer) and organic solvents (e.g., ethanol, methanol, isopropanol,acetonitrile, trifluoroacetic acid, diethylamine, etc.), singly or as asuitable mixture of them, to isolate the individual optical isomers. Inthe case of gas chromatography, for example, a chiral column such asCP-Chirasil-DeX CB (manufactured by GL Science Co.), and the like isused for isolation.

3) Diastereomer Method

A racemic mixture is chemically reacted with an optically-active reagentto give a mixture of diastereomer, which is subjected to ordinaryseparation means (e.g., fractional recrystallization, chromatography,etc.) to give single compounds. The thus-isolated single compounds arethen chemically processed, for example, through hydrolysis to therebyremove the optically-active reagent site from the compounds to obtainoptical isomers. For example, where compound (I) has a hydroxy group ora primary or secondary amino group in the molecule, it is condensed withan optically-active organic acid (e.g., MTPA[α-methoxy-α-(trifluoromethyl)phenyl-acetic acid], (−)-menthoxyaceticacid, etc.) or the like to give the corresponding ester-type oramide-type diastereomer. On the other hand, where compound (I) has acarboxylic acid group, it is condensed with an optically active amine oralcohol reagent to give the corresponding amide-type or ester-typediastereomer, respectively. The thus-isolated diastereomer is thensubjected to acidic or basic hydrolysis, through which it is convertedinto the optical isomer of the original compound.

The prodrug of the compound (I) means a compound capable of beingconverted to the compound (I) in vivo by the action of an enzyme orgastric juice and the like under physiological conditions, namely acompound capable of being converted to the compound (I) upon enzymaticoxidation, reduction or hydrolysis and the like, or a compound capableof being converted to the compound (I) upon hydrolysis and the like bygastric juice and the like. As the prodrug of the compound (I),compounds derived by acylation, alkylation or phosphorylation of theamino group of the compound (I) (e.g., compounds derived byeicosanoylation, alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation ortert-butylation of the amino group of the compound (I) etc.); compoundsderived by acylation, alkylation, phosphorylation or boration of thehydroxy group of the compound (I) (e.g., compounds derived byacetylation, palmitoylation, propanoylation, pivaloylation,succinylation, fumarylation, alanylation ordimethylaminomethylcarbonylation of the hydroxy group of the compound(I), etc.); and compounds derived by esterification or amidation of thecarboxyl group of the compound (I) (e.g., compounds derived by ethylesterification, phenyl esterification, carboxymethyl esterification,dimethylaminomethyl esterification, pivaloyloxymethyl esterification,ethoxycarbonyloxyethyl esterification, phthalidyl esterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification, or methylamidation of thecarboxyl group of the compound (I) etc.), and the like can be mentioned.These compounds can be produced from the compound (I) by methods knownper se.

The prodrug of the compound (I) may be one capable of being converted tothe compound (I) under physiological conditions, as described in“Iyakuhin no Kaihatsu (Development of Drugs)”, vol. 7, MolecularDesigning, published by Hirokawa Shoten, 1990, pages 163-198.

For example, the compound (I) can be produced according to [ProductionMethod 1] to [Production Method 3], which are described in detail below,or an analogous method thereto.

In the following [Production Method 1] to [Production Method 3], thecompounds for the starting material compound may be used in the form ofa salt, respectively. As such salt, those exemplified as the salt of theaforementioned compound (I) can be used.

In the following production methods, when alkylation reaction,hydrolysis reaction, amination reaction, esterification reaction,amidation reaction, esterification reaction, etherification reaction,oxidation reaction, reduction reaction etc. are to be conducted, thesereactions are carried out according to methods known per se, forexample, those described in Organic Functional Group Preparations, 2ndEd., Academic Press Inc., 1989; Comprehensive Organic Transformations,VCH Publishers Inc., 1989; and the like.

[Production Method 1]

The compound (I) is produced by, for example, the following amidationreaction.(Amidation Reaction)

wherein the symbols in the formula are as defined above.

The “amidation reaction” includes “a method using a dehydrationcondensing agent” and “a method using a reactive derivative of carboxy”described below.

i) Method Using a Dehydration Condensing Agent

The compound (III), 1 to 5 equivalents of compound (II) and 1 to 2equivalents of dehydration condensing agent are reacted in an inertsolvent. Where necessary, the reaction may be carried out in theco-presence of 1 to 1.5 equivalents of 1-hydroxybenzotriazole (HOBT)and/or catalytic amount to 5 equivalents of a base.

As the “dehydration condensing agent”, for example,dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) andthe like can be mentioned. Of these, WSC is preferable.

As the “inert solvent”, for example, nitrile solvents (preferablyacetonitrile), amide solvents (preferably DMF), halogenated hydrocarbonsolvents (preferably dichloromethane), ether solvents (preferably THF)and the like can be mentioned. Two or more kinds of these can be mixedin an appropriate ratio and used.

As the “base”, for example;

-   1) strong bases such as alkali metal or alkaline earth metal    hydrides (e.g., lithium hydride, sodium hydride, potassium hydride,    calcium hydride, etc.), alkali metal or alkaline earth metal amides    (e.g., lithium amide, sodium amide, lithium diisopropylamide,    lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium    hexamethyldisilazide, potassium hexamethyldisilazide, etc.), alkali    metal or alkaline earth metal lower-alkoxides (e.g., sodium    methoxide, sodium ethoxide, potassium tert-butoxide, etc.), and the    like;-   2) inorganic bases such as alkali metal or alkaline earth metal    hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium    hydroxide, barium hydroxide, etc), alkali metal or alkaline earth    metal carbonates (e.g., sodium carbonate, potassium carbonate,    cesium carbonate, etc), alkali metal or alkaline earth metal    hydrogencarbonates (e.g., sodium hydrogencarbonate, potassium    hydrogencarbonate, etc.) and the like; and-   3) organic bases such as amines (e.g., triethylamine,    diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine,    DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN    (1,5-diazabicyclo[4.3.0]non-5-ene) and the like); basic heterocyclic    compound (e.g., pyridine, imidazole, 2,6-lutidine and the like) and    the like,    and the like can be mentioned.

Of the above-mentioned base, triethylamine, 4-dimethylaminopyridine andthe like are preferable.

The reaction temperature is generally room temperature (1 to 30° C.,hereinafter the same). The reaction time is, for example, 10 hrs to 24hrs.

ii) Method Using a Reactive Derivative of Carboxy

The reactive derivative of the compound (II) and 1 to 5 equivalents(preferably 1 to 3 equivalents) of the compound (III) are reacted in aninert solvent. Where necessary, the reaction may be carried out in theco-presence of 1 to 10 equivalents, preferably 1 to 3 equivalents, of abase.

As the “reactive derivative” of the compound (II), for example, acidhalide (e.g., acid chloride, acid bromide, etc.), mixed acid anhydride(e.g., acid anhydride with C₁₋₆ alkyl-carboxylic acid, C₆₋₁₀aryl-carboxylic acid or C₁₋₆ alkyl-carbonic acid, etc.), activated ester(e.g., ester with phenol optionally having substituent(s),1-hydroxybenzotriazole or N-hydroxysuccinimide, etc.) and the like canbe mentioned.

As the “substituent(s)” of the “phenol optionally havingsubstituent(s)”, for example, halogen atom (e.g., fluorine, chlorine,bromine, iodine, etc.), nitro, optionally halogenated C₁₋₆ alkyl andoptionally halogenated C₁₋₆ alkoxy can be mentioned. The number of thesubstituents is, for example, 1 to 5.

As the “optionally halogenated C₁₋₆ alkyl” and “optionally halogenatedC₁₋₆ alkoxy”, those exemplified for the aforementioned Ra¹ can be usedrespectively.

As specific examples of the “phenol optionally having substituent(s)”,phenol, pentachlorophenol, pentafluorophenol, p-nitrophenol and the likecan be mentioned. The reactive derivative is preferably acid halide.

As the “inert solvent”, for example, ether solvents, halogenatedhydrocarbon solvents, aromatic solvents, nitrile solvents, amidesolvents, ketone solvents, sulfoxide solvents, water and the like can bementioned. These may be used on mixing two or more kinds at a suitableproportion. Of these, preferred are acetonitrile, THF, dichloromethane,chloroform, and the like.

As the “base”, those similar to the aforementioned can be used. The baseis preferably sodium hydride, potassium carbonate, sodium carbonate,sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate,potassium hydrogen carbonate, triethylamine, pyridine and the like.

The reaction temperature is generally −20° C. to 50° C., preferably roomtemperature. The reaction time is generally 5 min to 40 hrs., preferably1 to 18 hrs.

The aforementioned compound (III) can be produced by a method known perse, such as the method described in WO01/82925 or a method analogousthereto.

The aforementioned compound (II) can be produced by methods known perse.

[Production Method 2]

The compound (Ia) wherein Ar¹ is a non-aromatic cyclyl amino groupoptionally having substituent(s) can be also produced by, for example,the following ureation reaction.(Ureation Reaction)

wherein Ar^(1a) is a non-aromatic cyclyl amino group optionally havingsubstituent(s) and other symbols are as defined above.

As the “non-aromatic cyclyl amino group optionally havingsubstituent(s)” for Ar^(1a), of the “cyclic group optionally havingsubstituent(s)” exemplified for the aforementioned Ar, those wherein acyclic group is a non-aromatic cyclyl amino group, can be used. Here, asspecific examples of the non-aromatic cyclyl amino group, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and the like canbe mentioned.

This reaction is carried out by reacting compound (Ib) with 1 to 5equivalents (preferably 1 to 1.5 equivalents) of compound (IV) in theco-presence of a base in an inert solvent.

As the “base”, those exemplified in the aforementioned “method using adehydration condensing agent” can be used. The base is preferablypotassium carbonate, sodium carbonate, sodium hydroxide, potassiumhydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate,triethylamine, pyridine and the like. The amount of the base to be usedis, for example, 1 to 10 equivalents, preferably 1 to 3 equivalents,relative to compound (Ib).

As the “inert solvent”, for example, alcohol solvents, ether solvents,halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents,amide solvents, ketone solvents, sulfoxide solvents, water and the likecan be mentioned. Two or more kinds of these can be mixed in anappropriate ratio and used of these, acetonitrile, DMF, acetone,ethanol, pyridine and the like are preferable.

The reaction temperature is generally about −20° C. to 100° C,preferably room temperature to 80° C. The reaction time is, for example,about 0.5 hr to 1 day.

The aforementioned compound (IV) can be produced by a method known perse.

In addition, compound (Ib) can be produced by, for example, according tothe aforementioned [Production Method 1].

[Production Method 3]

The compound (Id) wherein, in the formula (I), Ar¹ is a grouprepresented by the formula: Ar³—Ar^(2a)— (wherein Ar^(2a) is an aromaticgroup optionally having substituent(s) and Ar³ is as defined above) canbe also produced by, for example, the following aryl-coupling reaction.(Aryl-Coupling Reaction)

wherein L¹ is hydroxy or C₁₋₆ alkoxy; L² is a halogen atom ortrifluoromethanesulfonyloxy; and other symbols are as defined above.

As the C₁₋₆ alkoxy for L¹, for example, methoxy, ethoxy, propoxy,butoxy, pentyloxy, hexyloxy and the like can be mentioned.

As the halogen atom for L², for example, fluorine, chlorine, bromine,iodine and the like can be mentioned. Of these, chlorine and bromine arepreferable.

As the “aromatic group optionally having substituent(s)” for Ar^(2a), ofthe “cyclic group optionally having substituent(s)” for theaforementioned Ar², those wherein the cyclic group is an aromatic group,can be mentioned.

In compound (Id), a compound wherein Ar³ and Ar^(2a) are each a phenyloptionally having substituent(s) and Ar³—Ar^(2a)— is a biphenylyloptionally having substituent(s), is particularly preferable.

The aryl-coupling reaction can be carried out according to a methodknown per se, for example, the method described in Acta. ChemicaScandinavia, pp. 221-230 (1993) and the like, or a method analogousthereto.

This reaction is carried out by, for example, reacting compound (Ic)with 1 to 3 equivalents (preferably 1 to 1.5 equivalents) of compound(V) in the presence of a base and a transition metal catalyst in aninert solvent.

As the “base”, those exemplified in the aforementioned “method using adehydration condensing agent” can be used. As the base, sodiumcarbonate, sodium hydrogen carbonate and the like are preferable.

The amount of the “base” to be used is, for example, generally about 1to 10 equivalents relative to compound (Ic)

As the “transition metal catalyst”, for example, palladium catalyst,nickel catalyst and the like can be mentioned. As the “palladiumcatalyst”, for example, tetrakis(triphenylphosphine)palladium(0),palladium acetate, bis(triphenylphosphine)palladium(II) chloride,palladium-carbon and the like can be mentioned. As the “nickelcatalyst”, for example, tetrakis(triphenylphosphine)nickel (0) and thelike can be mentioned.

The amount of the “transition metal catalyst” to be used is generallyabout 0.01 to 1 equivalent, preferably about 0.01 to 0.5 equivalent,relative to compound (Ic).

The reaction temperature is generally from room temperature to 150° C.,preferably about 80° C. to 150° C. The reaction time is, for example,about 1 to 48 hrs.

As the “inert solvent”, for example, water, alcohol solvents, aromaticsolvents and the like can be mentioned. Two or more kinds of these canbe mixed in an appropriate ratio for use. Of these, a single solvent ofwater, ethanol, toluene and the like or a mixed solvent of two or moreof these is preferable.

The aforementioned compound (V) can be produced by a method known perse.

In addition, compound (Ic) can be produced according to, for example,the aforementioned [Production Method 1].

As the aforementioned “alcohol solvent”, for example, methanol, ethanol,isopropanol, tert-butanol and the like can be used.

As the aforementioned “ether solvent”, for example, diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane and the like canbe used.

As the aforementioned “halogenated hydrocarbon solvent”, for example,dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachlorideand the like can be used.

As the aforementioned “aromatic solvent”, for example, benzene, toluene,xylene, pyridine and the like can be used.

As the aforementioned “hydrocarbon solvent”, for example, hexane,pentane, cyclohexane and the like can be used.

As the aforementioned “amide solvent”, for example,N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidoneand the like can be used.

As the aforementioned “ketone solvent”, for example, acetone, methylethyl ketone and the like can be used.

As the aforementioned “sulfoxide solvent”, for example, dimethylsulfoxide (DMSO) and the like can be used.

As the aforementioned “nitrile solvent”, for example, acetonitrile,propionitrile and the like can be used.

In the compound (I) thus obtained, the functional group in a moleculecan be also converted to the object functional group by combiningchemical reactions known per se. As the examples of such chemicalreaction, oxidation reaction, reduction reaction, alkylation reaction,hydrolysis reaction, amination reaction, esterification reaction,aryl-coupling reaction, deprotection reaction and the like can bementioned.

In each of the aforementioned reactions, when the starting materialcompound has an amino group, carboxy group, hydroxy group or carbonylgroup as a substituent, a protecting group generally used in peptidechemistry and the like may be introduced and an object compound can beobtained by removing the protecting group after the reaction wherenecessary.

Examples of the protecting group for amino group include formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl and the like), C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl and the like), benzoyl, C₇₋₁₀ aralkyl-carbonyl(e.g., benzylcarbonyl and the like), C₇₋₁₄ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl and the like), trityl,phthaloyl, N,N-dimethylaminomethylene, silyl (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl and the like), C₂₋₆ alkenyl (e.g., 1-allyl andthe like) and the like. These groups may be substituted by 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), C₁₋₆alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) or nitro etc.

Examples of the protecting group for carboxy group include C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), C₇₋₁₁aralkyl (e.g., benzyl, etc.), phenyl, trityl, silyl (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C₂₋₆ alkenyl(e.g., 1-allyl, etc.) and the like. These groups may be substituted by 1to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.),C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) or nitro etc.

Examples of the protecting group for hydroxy group include C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.),phenyl, trityl, C₇₋₁₀ aralkyl (e.g., benzyl, etc.), formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl, etc.), benzoyl, C₇₋₁₀aralkyl-carbonyl (e.g., benzylcarbonyl, etc.), 2-tetrahydropyranyl,2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl, triethylsilyl,dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl,etc.), C₂₋₆ alkenyl (e.g., 1-allyl, etc.) and the like. These groups maybe substituted by 1 to 3 of halogen atoms (e.g., fluorine, chlorine,bromine, iodine, etc.), C₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl,etc.), C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) or nitro etc.

Examples of the protecting group for carbonyl group include cyclicacetal (e.g., 1,3-dioxane, etc.), and acyclic acetal (e.g., di-C₁₋₆alkylacetal, etc.) and the like.

Removal of the above protecting groups can be carried out in accordancewith methods known per se such as those described in Protective Groupsin Organic Synthesis, published by John Wiley and Sons (1980) and thelike. For instance, the methods using acid, base, ultraviolet light,hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide(e.g., trimethylsilyl iodide, trimethylsilyl bromide, etc.) and thelike, a reduction method and the like can be used.

The compound (I) can be isolated and purified by methods known per sesuch as solvent extraction, changing of liquid properties,transdissolution, crystallization, recrystallization, chromatography,and the like. It is also possible to isolate and purify the startingmaterial compounds of a compound (I), or their salts using the sameknown methods as above, but they can be also used as starting materialsin the next process as a reaction mixture without being isolated.

Inasmuch as the compound (I) and a prodrug thereof (hereinafterabbreviated as the compound of the present invention) has a superior MCHreceptor antagonistic action, it is useful as an agent for theprophylaxis or treatment of diseases caused by MCH. In addition, thecompound of the present invention shows low toxicity (e.g., acutetoxicity, chronic toxicity, genetic toxicity, reproductive toxicity,cardiac toxicity, drug interaction, carcinogenicity), and superior oralabsorption performance and transfer into the brain.

Accordingly, the compound of the present invention is safelyadministered as an agent for the prophylaxis or treatment of diseasescaused by MCH to mammals (e.g., rat, mouse, guinea pig, rabbit, sheep,horse, pig, cow, monkey, human, etc.).

The diseases caused by MCH include, for example, obesity [e.g.,malignant mastocytosis, exogenous obesity, hyperinsulinar obesity,hyperplasmic obesity, hypophyseal adiposity, hypoplasmic obesity,hypothyroid obesity, hypothalamic obesity, symptomatic obesity,infantile obesity, upper body obesity, alimentary obesity, hypogonadalobesity, systemic mastocytosis, simple obesity, central obesity and thelike], hyperphagia, emotional disorder, sexual dysfunction, depression,anxiety and the like.

The compound of the present invention is also useful as an agent for theprophylaxis or treatment of life-style related diseases such asdiabetes, diabetic complications (e.g., diabetic retinopathy, diabeticneuropathy, diabetic nephropathy, etc.), arteriosclerosis, gonarthritisand the like.

Furthermore, the compound of the present invention is also useful as afeeding deterrent.

The compound of the present invention can be also concurrently used withdiet therapy (e.g., diet therapy for diabetes, etc.), or an exercisetherapy.

The compound of the present invention can be used for the prophylaxis ortreatment of pigmentation disorder based on abnormality of melanin ormelanocyte. Here, as the pigmentation disorder, pigment proliferation,pigment decrease and the like can be mentioned. As the pigmentproliferation, drug pigmentation caused by antitumor agent and the like;chromatosis and incompetence of pigment associated with diseases such asendocrine metabolism disorder (e.g., Addison's disease), geneticdiseases, chronic hepatopathy, kidney failure, acanthosis nigricans,systemic scleroderma and the like; and the like can be mentioned. As thepigment decrease, phenylketonuria, systemic or localized albinism,foliaceous leukoderma or leukoderma vulgaris associated with tuberoussclerosis; depigmentation associated with systemic scleroderma and thelike can be mentioned.

The compound of the present invention can be used for the prophylaxis ortreatment of depigmentation due to chloasma, ephelides, sunburn and thelike; and further, hyperpigmentation or hypopigmentation for cosmeticpurposes.

The pharmaceutical agent of the present invention can be produced byformulating the compound of the present invention as it is or along witha pharmacologically acceptable carrier according to a method known perse.

As the pharmacologically acceptable carrier, various organic orinorganic carrier substance conventionally used as a material forpreparation, such as excipient, lubricant, binder, disintegrant forsolid preparation; solvent, dissolution aids, suspending agent,isotonicity agent, buffer, soothing agent and the like for liquidpreparation are mentioned. In formulating a preparation, additives suchas preservative, antioxidant, coloring agent, sweetening agent,absorbent, moistening agent and the like can be also added as necessary.

Examples of the excipient include lactose, saccharose, D-mannitol,starch, cornstarch, crystalline cellulose, light silicic anhydride andthe like.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, saccharose,D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethyl cellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethyl cellulose,carboxymethyl cellulose calcium, crosscarmellose sodium, carboxymethylstarch sodium, low substituted hydroxypropyl cellulose (L-HPC) and thelike.

Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil and the like.

Examples of the dissolution aids include polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate and thelike.

Examples of the suspending agent include surfactant such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride, glycerylmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose and the like, and the like.

Examples of the isotonicity agent include glucose, D-sorbitol, sodiumchloride, glycerine, D-mannitol and the like.

Examples of the buffer include buffers such as phosphate, acetate,carbonate, citrate and the like and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include p-oxybenzoate, chlorobutanol,benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid andthe like.

Examples of the antioxidant include sulfite, ascorbic acid and the like.

Examples of the dosage form of a pharmaceutical agent of the presentinvention include oral preparations such as tablet (inclusive ofsugar-coated tablet, film coated tablet, sublingual tablet and orallydisintegrable tablet), powder, granule, capsule (inclusive of softcapsule), liquid and the like; parenteral preparations such as injection(e.g., subcutaneous injection, intravenous injection, intramuscularinjection, intraperitoneal injection, etc.), external preparation (e.g.,transnasal administration preparation, percutaneous preparation,ointment, etc.), suppository (e.g., rectal suppository, pessary, etc.),sustained-release preparation (e.g., sustained-release microcapsule,etc.), pellet, drops, transpulmonary agent (inhalant), eye drops and thelike; and the like, and can be safely administered orally orparenterally (e.g., topical, rectal, intravenous administration, etc.).

The content of the compound of the present invention in thepharmaceutical agent of the present invention is, for example, about 0.1to 100 wt % of the whole amount of pharmaceutical agent.

The dose of the compound of the present invention is appropriatelydetermined according to the administration subject, administrationroute, disease and the like.

For example, when the compound of the present invention is orallyadministered to adult patients (body weight about 60 kg) with obesity,the daily dose is about 0.1 to about 500 mg, preferably about 1 to about100 mg, more preferably about 5 to about 100 mg, which dose isadministered once or divided in several times a day.

With the aim of, for example, “enhancement of treatment effect of thecompound of the present invention against obesity”, “enhancement oftreatment effect of the compound of the present invention againstdepression or anxiety”, “reduction of the amount of the compound of thepresent invention to be used” and the like, the compound of the presentinvention may be used in combination with a combination drug, which doesnot exert an adverse influence on the compound of the present invention.As such combination drug, for example, “antidiabetic agent”, “agent fortreating diabetic complication”, “anti-obesity agent other than MCHantagonist”, “agent for treating hypertension”, “agent for treatinghyperlipidemia (agent for treating arteriosclerosis), “agent fortreating arthritis”, “anti-anxiety agent”, “antidepressant” and the likeare mentioned. These combination drugs may be used in a combination oftwo or more thereof in an appropriate proportion.

As the above-mentioned “antidiabetic agent”, for example, insulinsensitizer, insulin secretagogue, biguanide agent, insulin,α-glucosidase inhibitor, β3 adrenergic receptor agonist and the like arementioned.

As the insulin sensitizer, for example, pioglitazone or a salt thereof(preferably hydrochloride), troglitazone, rosiglitazone or a saltthereof (preferably maleate), Reglixane (JTT-501), GI-262570,Netoglitazone (MCC-555), YM-440, DRF-2593, BM-13-1258, KRP-297,R-119702, CS-011, FK-614, compounds described in WO99/58510 (e.g.,(E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid), Tesaglitazar (AZ-242), Ragaglitazar (NN-622), BMS-298585,ONO-5816, BM-13-1258, LM-4156, MBX-102, LY-519818, MX-6054, LY-510929and the like are mentioned.

As the insulin secretagogue, for example, sulfonylurea agent ismentioned. Specific examples of the sulfonylurea agent includetolbutamide, chlorpropamide, tolazamide, acetohexamide, glyclopyramideand ammonium salt thereof, glibenclamide, gliclazide, glimepiride andthe like.

In addition to the above, insulin secretagogue includes, for example,repaglinide, nateglinide, mitiglinide (KAD-1229), JTT-608 and the like.

As the biguanide agent, for example, metformin, buformin, phenformin, asalt thereof (e.g., hydrochloride, fumarate, succinate) and the like arementioned.

As the insulin, for example, animal insulin extracted from pancreas ofcow and swine; semi-synthetic human insulin enzymatically synthesizedfrom insulin extracted from pancreas of swine; human insulin geneticallysynthesized using Escherichia coli or yeast; and the like are mentioned.As insulin, insulin zinc containing 0.45 to 0.9 (w/w) % of zinc;protamine insulin zinc produced from zinc chloride, protamine sulfateand insulin, and the like can be also used. Moreover, insulin can be afragment or derivative thereof (e.g., INS-1, etc.).

While insulin includes various types such as very rapid acting type,short-acting type, biphasic type, intermediate-acting type, extendedtype and the like, which can be determined depending on the diseasestate of patients.

As the α-glucosidase inhibitor, for example, acarbose, voglibose,miglitol, emiglitate and the like are mentioned.

As the β3 adrenergic receptor agonist, for example, AJ-9677, BMS-196085,SB-226552, AZ40140, CP-331684 and the like are mentioned.

In addition to the above, the “antidiabetic agent” includes, forexample, ergoset, pramlintide, leptin, BAY-27-9955 and the like.

As the above-mentioned “agent for treating diabetic complication”, forexample, aldose reductase inhibitor, glycation inhibitor, protein kinaseC inhibitor and the like are mentioned.

As the aldose reductase inhibitor, for example, tolrestat; epalrestat;imirestat; zenarestat; fidarestat (SNK-860); zopolrestat; ARI-509;AS-3201 and the like are mentioned.

As the glycation inhibitor, for example, pimagedine and the like arementioned.

As the protein kinase C inhibitor, for example, NGF, LY-333531 and thelike are mentioned.

In addition to the above, the “agent for treating diabetic complication”includes, for example, alprostadil, tiapride hydrochloride, cilostazol,mexiletine hydrochloride, ethyl icosapentate, memantine, pimagedline(ALT-711), neurotrophic factor and enhancer thereof (e.g., NGF, NT-3,BDNF, neurotrophin production/secretion promoters (e.g.,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole,etc.) described in WO01/14372 and the like), neuranagenesis acceleratingdrug (e.g., Y-128, etc.) and the like.

As the above-mentioned “anti-obesity agent other than MCH antagonist”,for example, lipase inhibitor, anorectic agent, β3 adrenergic receptoragonist and the like are mentioned.

As the lipase inhibitor, for example, orlistat, ATL-962 and the like arementioned.

As the anorectic agent, for example, mazindol, dexfenfluramine,fluoxetine, sibutramine, biamine and the like are mentioned.

As the β3 adrenergic receptor agonist, “β3 adrenergic receptor agonist”exemplified for the above-mentioned “antidiabetic agent” can bementioned.

In addition to the above, the “anti-obesity agent other than MCHantagonist” includes, for example, lipstatin and the like.

As the above-mentioned “agent for treating hypertension”, for example,angiotensin converting enzyme inhibitor, calcium antagonist, potassiumchannel opener, angiotensin II antagonist and the like are mentioned.

As the angiotensin converting enzyme inhibitor, for example, captoril,enalapril, alacepril, delapril (hydrochrolide), lisinopril, imidapril,benazepril, cilazapril, temocapril, trandolapril, manidipine(hydrochrolide) and the like are mentioned.

As the calcium antagonist, for example, nifedipine, amlodipine,efonidipine, nicardipine and the like are mentioned.

As the potassium channel opener, for example, levcromakalim, L-27152, AL0671, NIP-121 and the like are mentioned.

As the angiotensin II antagonist, for example, losartan, candesartancilexetil, valsartan, irbesartan, CS-866, E4177 and the like arementioned.

As the above-mentioned “agent for treating hyperlipidemia (agent fortreating arteriosclerosis)”, for example, HMG-CoA reductase inhibitor,fibrate compound and the like are mentioned.

As the HMG-CoA reductase inhibitor, for example, pravastatin,simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil,cerivastatin, itavastatin, rosuvastatin (ZD-4522) or a salt thereof(e.g., sodium salt, calcium salt and the like) and the like arementioned.

As the fibrate compound, for example, bezafibrate, clinofibrate,clofibrate, simfibrate and the like are mentioned.

As the above-mentioned “agent for treating arthritis”, for example,ibuprofen and the like are mentioned.

As the above-mentioned “anti-anxiety agent”, for example,chlordiazepoxide, diazepam, oxazolam, medazepam, cloxazolam, bromazepam,lorazepam, alprazolam, fludiazepam and the like are mentioned.

As the above-mentioned “antidepressant”, for example, fluoxetine,fluvoxamine, imipramine, paroxetine, sertraline and the like arementioned.

The time of administration of the aforementioned combination drug is notlimited. The compound of the present invention and a combination drugmay be simultaneously administered to an administration subject oradministered in a staggered manner. The dose of the combination drug canbe determined according to the dose clinically employed, and can bedetermined as appropriate depending on the administration subject,administration route, disease, combination and the like.

The mode of administration of the combination drug is not particularlylimited, and may be any as long as the compound of the present inventionand combination drug are combined on administration. Such administrationmode is exemplified by 1) administration of a single preparationobtained by simultaneously formulating the compound of the presentinvention and combination drug, 2) simultaneous administration by thesame administration route of two kinds of preparations obtained byseparately formulating the compound of the present invention andcombination drug, 3) staggered administration by the same administrationroute of two kinds of preparations obtained by separately formulatingthe compound of the present invention and combination drug, 4)simultaneous administration by different administration routes of twokinds of preparations obtained by separately formulating the compound ofthe present invention and combination drug, 5) staggered administrationby different administration routes of two kinds of preparations obtainedby separately formulating the compound of the present invention andcombination drug (e.g., administration of compound of the presentinvention and combination drug in this order, and administration in thereversed order) and the like.

The admixing ratio of the compound of the present invention andcombination drug can be appropriately determined depending on theadministration subject, administration route, disease and the like.

Of compounds (I), since a compound wherein a group represented by thepartial structural formula: —CO—N(R)—C(Ra¹)(Ra²)—C(Ra³)(Ra⁴)— [whereinthe symbols in the formula are as defined above] is —CH₂—NH—CO—CH₂—,—NH—CO—CH₂—CH₂—, —NH—CO—CH═CH—, —CH₂—CH₂—NH—CO—, —NH—CO—CH₂—O—,—NH—CO—C(Ph)═CH—, —NH—CO—CH═C(4-Cl—Ph)—, —CH₂—CH₂—CO—NH—, —CH═CH—CO—NH—,—CH₂—CO—NH—CH₂—, —NH—CO—CH(CH₃)—O—, —SO₂—NH—CH₂—CH₂—, —SO₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—C≡C—, —CH₂—CH₂—CO—CH₂—, —CO—CH₂—CH₂—CO—, —CO—CH₂—CH₂—CH(OH)—,—CO—CH₂—CH═CH—, —CO—CH₂—CH₂—CH₂— or —CH₂—CH₂—CH₂—CO— [wherein Ph is aphenyl group and 4-Cl—Ph is a 4-chlorophenyl group], a salt thereof anda prodrug thereof (hereinafter sometimes to be abbreviated as compoundgroup A) have an MCH receptor antagonistic action, they can be used asagents for the prophylaxis or treatment of diseases caused by MCH inmammals in the same manner as the compound of the present invention.

Here, as the salt and a prodrug thereof, those exemplified as the saltof compound (I) and prodrug of compound (I) can be used. As specificexamples of compound group A, the compounds of the below-mentionedReference Examples 38-75, 90-114 and the like can be mentioned.

The compound group A can be produced in the same manner as in compound(I).

The compound group A can be formulated into preparations in the samemanner as in compound (I), and can be also used in combination with acombination drug.

The present invention is described in detail by way of the followingReference Examples, Examples, Formulation Example and ExperimentalExample. These are not intended to restrict the present invention, andmay be modified within the range not deviating from the scope of thisinvention.

The “room temperature” in the following Reference Examples and Examplesmeans a temperature of 0° C. to 30° C. For drying an organic layer,anhydrous magnesium sulfate or anhydrous sodium sulfate was employed.Unless otherwise specifically indicated, “%” means percent by weight.

The infrared spectrum was measured using Fourier transform infraredspectrophotometer by Diffuse Reflectance method.

FABMS(pos) is mass spectrum measured by the (+) method in the Fast AtomBombardment Mass Spectrometry.

The abbreviations used in the present specification mean the following.

-   s: singlet-   d: doublet-   t: triplet-   q: quartet-   m: multiplet-   br: broad-   J: coupling constant-   Hz: Hertz-   CDCl₃: deuterated chloroform-   DMSO-d₆: deuterated dimethyl sulfoxide-   THF: tetrahydrofuran-   DMF: N,N-dimethylformamide-   DMSO: dimethylsulfoxide-   WSCD: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-   ¹H-NMR: proton nuclear magnetic resonance (free compound is    generally used for measurement in CDCl₃)-   IR: infrared spectrum-   Me: methyl-   Et: ethyl-   HOBt: 1-hydroxy-1H-benzotriazole-   IPE: diisopropyl ether-   DMAP: 4-dimethylaminopyridine

REFERENCE EXAMPLE 1 3-[4-(methoxycarbonyl)phenyl]propionic acid

To a solution of methyl 4-(3-methoxy-3-oxopropyl)benzoate (5.05 g, 22.7mmol) in methanol (120 ml) was added 1N aqueous sodium hydroxidesolution (22.7 ml) at 0° C., and the mixture was stirred at roomtemperature for 16 hrs. After the reaction mixture was concentrated, theresidue was dissolved in water, and the solution was washed with diethylether. To the aqueous layer was added 6N hydrochloric acid, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure, and the obtained residue wasdissolved in chloroform, and insoluble materials were filtered off. Thesolvent was evaporated under reduced pressure, and the obtained residuewas powderized with hexane to give the title compound (3.61 g) as apowder.

¹H-NMR (CDCl₃) δ: 2.71 (2H, d, J=8.0 Hz), 3.01 (2H, d, J=8.0 Hz), 3.90(3H, s), 7.28 (2H, d, J=8.0 Hz), 7.97 (2H, t, J=8.0 Hz).

REFERENCE EXAMPLE 2 methyl4-{2-[(tert-butoxycarbonyl)amino]ethyl}benzoate

A solution (120 ml) of 3-[4-(methoxycarbonyl)phenyl]propionic acid (5.00g, 24.0 mmol) obtained in Reference Example 1, triethylamine (4.34 ml,31.2 mmol) and DPPA (6.21 ml, 28.8 mmol) in tert-butanol was stirred at90° C. for 5 hrs, and the solvent was evaporated. Ethyl acetate wasadded to the residue and the mixture was washed with 10% aqueous citricacid solution, saturated aqueous potassium carbonate solution andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:1), and powderized with hexane to give the titlecompound (2.46 g).

¹H-NMR (DMSO-d₆) δ: 1.35 (9H, s), 2.76 (2H, d, J=7.2 Hz), 3.17 (2H, m),3.83 (3H, s), 6.90 (1H, d, J=5.4 Hz), 7.34 (2H, d, J=8.4 Hz), 7.87 (2H,d, J=8.4 Hz).

REFERENCE EXAMPLE 3 tert-butyl2-[4-(1-pyrrolidinylmethyl)phenyl]ethylcarbamate

To a solution (10 ml) of methyl4-{2-[(tert-butoxycarbonyl)amino]ethyl}benzoate (550 mg, 1.97 mmol)obtained in Reference Example 2 in tetrahydrofuran was added lithiumaluminum hydride at 0° C., and the mixture was stirred at roomtemperature for 1 hr. To the reaction mixture was added ethyl acetateand the mixture was washed with 0.5N hydrochloric acid and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby alumina column chromatography (developing solvent; ethyl acetate) togive a colorless oil. To a solution (10 ml) of the obtained oil (495 mg,1.97 mmol) and triethylamine (274 ml, 1.97 mmol) in dimethylformamidewas added methanesulfonyl chloride (152 ml, 1.97 mmol) at 0° C., and themixture was stirred for 1 hr. Pyrrolidine (329 ml, 3.94 mmol) andpotassium carbonate (816 mg, 5.91 mmol) were added and the mixture wasstirred at 60° C. for 16 hrs. To the reaction mixture was added 0.5Nhydrochloric acid, and the mixture was washed with diethyl ether. Theaqueous layer was basified with potassium carbonate and extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the obtained residue was purified by alumina columnchromatography (developing solvent; ethyl acetate) to give the titlecompound (527 mg).

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 1.78 (4H, m), 2.55 (4H, m), 2.77 (2H, t,J=7.0Hz), 3.36 (2H, m), 3.58 (2H, s), 4.55 (1H, s), 7.12 (2H, d, J=7.8Hz), 7.25 (2H, d, J=7.8 Hz).

REFERENCE EXAMPLE 4 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine

To tert-butyl 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylcarbamate (526 mg,1.73 mmol) obtained in Reference Example 3 was added trifluoroaceticacid (9 ml), and the mixture was stirred for 2 hrs. The mixture wasconcentrated under reduced pressure, and ethyl acetate was added to theresidue. The mixture was washed with saturated aqueous potassiumcarbonate solution and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure to give thetitle compound (239 mg).

¹H-NMR (CDCl₃) δ: 1.80 (4H, m), 2.50 (4H, m), 2.74 (2H, m), 2.96 (2H,m), 3.59 (2H, s), 7.14 (2H, d, J=8.0 Hz), 7.26 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 5 N-[4-(2-aminoethyl)benzyl]-N,N-dimethylaminetrifluoroacetate

The title compound was obtained by similar operations as in ReferenceExample 3 and Reference Example 4 and using methyl4-{2-[(tert-butoxycarbonyl)amino]ethyl}benzoate obtained in ReferenceExample 2.

¹H-NMR (CDCl₃) δ: 2.24 (6H, s), 2.79 (2H, t, J=7.2Hz), 2.99 (2H, t,J=7.2Hz), 3.42 (2H, s), 4.75 (3H, br), 7.12 (2H, m), 7.19 (2H, m).

REFERENCE EXAMPLE 6 2-[4-(1-piperidinylmethyl)phenyl]ethylaminedihydrochloride

The title compound was obtained by similar operations as in ReferenceExample 3 and Reference Example 4 and using methyl4-{2-[(tert-butoxycarbonyl)amino]ethyl}benzoate obtained in ReferenceExample 2.

¹H-NMR (DMSO-d₆) δ: 1.60-1.80 (6H, m), 2.80-3.30 (8H, m) 4.20 (2H, d,J=4.4 Hz), 7.33 (2H, d, J=8.1 Hz), 7.59 (2H, d, J=8.1 Hz), 8.18 (2H,br).

REFERENCE EXAMPLE 72-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethylamine trihydrochloride

The title compound was obtained by similar operations as in ReferenceExample 3 and Reference Example 4 and using methyl4-{2-[(tert-butoxycarbonyl)amino]ethyl}benzoate obtained in ReferenceExample 2.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 2.80-3.20 (4H, m), 3.20-3.80 (8H, m),4.27 (2H, br), 7.34 (2H, d, J=7.8 Hz), 7.58 (2H, d, J=7.8 Hz), 8.10 (2H,br).

REFERENCE EXAMPLE 82-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethylaminedihydrochloride

The title compound was obtained by similar operations as in ReferenceExample 3 and Reference Example 4 and using methyl4-{2-[(tert-butoxycarbonyl)amino]ethyl}benzoate obtained in ReferenceExample 2.

¹H-NMR (DMSO-d₆) δ: 1.55 (6H, d, J=6.2 Hz), 1.74 (6H, m), 2.96 (4H, m),3.43 (2H, m), 4.42 (2H, d, J=1.9 Hz), 7.36 (2H, d, J=8.1 Hz), 7.52 (2H,d, J=8.1 Hz), 8.25 (3H, br), 10.85 (1H, s).

REFERENCE EXAMPLE 9 2-[4-(1-azepanylmethyl)phenyl]ethylaminedihydrochloride

The title compound was obtained by similar operations as in ReferenceExample 3 and Reference Example 4 and using methyl4-{2-[(tert-butoxycarbonyl)amino]ethyl}benzoate obtained in ReferenceExample 2.

¹H-NMR (DMSO-d₆) δ: 1.60 (4H, m), 1.84 (4H, m), 2.98 (6H, m), 3.26 (2H,m), 4.27 (2H, d, J=5.5 Hz), 7.33 (2H, d, J=8.1 Hz), 7.65 (2H, d, J=8.1Hz), 8.31 (3H, br), 11.20 (1H, s).

REFERENCE EXAMPLE 10 tert-butyl2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylcarbamate

To a solution of tert-butyl 2-(4-formylphenyl)ethylcarbamate (3.0 g,12.0 mmol), 2-methylpyrrolidine (1.44 ml, 14.4 mmol) and acetic acid(1.4 ml, 24.0 mmol) in THF (100 ml) was added sodiumtriacetoxyborohydride (5.1 g, 24.0 mmol), and the mixture was stirred atroom temperature for 16 hrs. 10% Sodium hydrogencarbonate solution (100ml) was added to the reaction solution, and the mixture was extractedwith ethyl acetate (200 ml). The extract was washed with saturatedbrine, and dried over magnesium sulfate, and solvent was evaporatedunder reduced pressure. The residue was purified by alumina columnchromatography (developing solvent; hexane:ethyl acetate=4:1) to givethe title compound (3.10 g).

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=6.0 Hz), 1.39-1.51 (2H, m), 1,44 (9H,s), 1.59-1.75 (2H, m), 1.88-1.99 (1H, m), 2.34-2.41 (1H, m), 2.77 (2H,t, J=6.9 Hz), 2.87-2.94 (1H, m), 3.10 (1H, d, J=12.8 Hz), 3.35-3.37 (2H,q like), 3.99 (1H, d, J=12.8 Hz), 4.53 (1H, br), 7.13 (2H, d, J=8.1 Hz),7.25 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 112-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylamine dihydrochloride

To a solution of tert-butyl2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylcarbamate (3.10 g,9.70 mmol) obtained in Reference Example 10 in methanol (50 ml) wasadded 4N hydrogen chloride-ethyl acetate (60 ml), and the mixture wasstirred for 16 hrs, and concentrated under reduced pressure to give thetitle compound (2.8 g).

¹H-NMR (DMSO-d₆) δ: 1.37 (3H, d, J=6.6 Hz), 1.63-1.96 (3H, m), 2.15-2.24(1H, m), 2.80-3.22 (6H, m), 3.24-3.46 (1H, m), 4.10 (1H, m), 4.49 (1H,m), 7.33 (2H, d, J=8.1 Hz), 7.60 (2H, d, J=8.1 Hz), 8.23 (2H, br).

REFERENCE EXAMPLE 12 ethyl 4-(3-ethoxy-1-methyl-3-oxopropyl)benzoate

Ethyl 4-acetylbenzate (5.00 g, 26.0 mmol) was added to a solution (130ml) of ethyl diethylphosphonoacetate (6.71 ml, 33.8 mmol) andtert-butoxy potassium (4.38 g, 39.0 mmol) in tetrahydrofuran at 0° C.,and the mixture was stirred at room temperature for 16 hrs. Ethylacetate was added to the reaction mixture, and the mixture was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the obtained residuewas purified by NH-silica gel column chromatography (developing solvent;ethyl acetate). The mixture of the obtained oil and 10% palladium carbon(1 g) in ethanol (150 ml) was stirred under a hydrogen atmosphere for 2hrs, and filtered through celite. The solvent was evaporated underreduced pressure, and the obtained residue was purified by NH-silica gelcolumn chromatography (developing solvent; ethyl acetate) to give thetitle compound (5.67 g).

¹H-NMR (CDCl₃) δ: 1.17 (3H, t, J=7.2 Hz), 1.31 (3H, d, J=6.6 Hz), 1.38(3H, d, J=7.2 Hz), 2.59 (2H, m), 3.32 (1H, m), 4.05 (2H, q, J=7.2 Hz),4.34 (2H, q, J=7.2 Hz), 7.28 (2H, d, J=6.6 Hz), 7.96 (2H, d, J=6.6 Hz).

REFERENCE EXAMPLE 13 tert-butyl2-[4-(1-pyrrolidinylmethyl)phenyl]propylcarbamate

The title compound was obtained by similar operations as in ReferenceExample 1, Reference Example 2 and Reference Example 3 and using ethyl4-(3-ethoxy-1-methyl-3-oxopropyl)benzoate obtained in Reference Example12.

¹H-NMR (CDCl₃) δ: 1.24 (3H, d, J=7.2 Hz), 1.41 (9H, s), 1.79 (4H, m),2.50 (4H, m), 2.93 (1H, m), 3.16, (1H, m), 3.40 (1H, m), 3.58 (2H, s),4.42 (1H, m), 7.13 (2H, d, J=7.8 Hz), 7.26 (2H, d, J=7.8 Hz).

REFERENCE EXAMPLE 14 2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine

The title compound was obtained by similar operations as in ReferenceExample 3 and Reference Example 4 and using tert-butyl2-(4-acetylphenyl)ethylcarbamate.

¹H-NMR (CDCl₃) δ: 1.38 (3H, d, J=6.6 Hz), 1.75 (4H, m) 2.34 (2H, m),2.53 (2H, m), 2.72 (2H, t, J=6.9 Hz), 2.93 (2H, t, J=6.6 Hz), 3.15 (1H,q, J=6.3 Hz), 7.12 (2H, d, J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 15 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine

The title compound was obtained by similar operations as in ReferenceExample 3 and Reference Example 4 and using tert-butyl2-(4-acetylphenyl)ethylcarbamate.

¹H-NMR (CDCl₃) δ: 1.34 (2H, m), 1.37 (3H, d, J=6.6 Hz), 1.54 (4H, m),1.86 (2H, m), 2.35 (4H, m), 2.72 (2H, t, J=6.9 Hz), 2.94 (2H, t, J=6.6Hz), 3.36 (1H, q, J=6.3 Hz), 7.12 (2H, d, J=8.1 Hz), 7.21 (2H, d, J=8.1Hz).

REFERENCE EXAMPLE 162-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamine

The title compound was obtained by similar operations as in ReferenceExample 3 and Reference Example 4 and using tert-butyl2-(4-acetylphenyl)ethylcarbamate.

ESIMS(pos) 233 [M+H]⁺

REFERENCE EXAMPLE 17 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine

The title compound was obtained by similar operations as in ReferenceExample 3 and Reference Example 4 and using tert-butyl2-(4-acetylphenyl)ethylcarbamate.

¹H-NMR (CDCl₃) δ: 1.16 (2H, m), 1.33 (3H, d, J=6.6 Hz), 1.57 (8H, m),2.61 (4H, m), 2.72 (2H, t, J=6.9 Hz), 2.96 (2H, t, J=6.6 Hz), 3.74 (1H,q, J=6.6 Hz), 7.12 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 182-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamine

The title compound was obtained by similar operations as in ReferenceExample 3 and Reference Example 4 and using tert-butyl2-(4-acetylphenyl)ethylcarbamate.

¹H-NMR (CDCl₃) δ: 1.22 (2H, m), 1.35 (3H, d, J=6.9 Hz), 2.52 (3H, s),2.41 (8H, m), 2.72 (2H, t, J=6.6 Hz), 2.95 (2H, t, J=6.6 Hz), 3.34 (1H,q, J=6.9 Hz), 7.12 (2H, d, J=8.1 Hz), 7.24 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 19 N-[2-(4-acetylphenyl)ethyl]-4-bromobenzamide

To a solution of 4-bromo-N-(2-phenylethyl)benzamide (10.0 g, 32.9 mmol)and acetyl chloride (3.04 ml, 42.7 mmol) in dichloromethane (80 ml) wasadded aluminum chloride (11.0 g, 82.2 mmol), and the mixture was stirredat room temperature for one day. The reaction mixture was poured intoice, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was concentrated under reduced pressure, and the obtainedresidue was powderized with isopropyl ether to give the title compound(9.79 g).

¹H-NMR (DMSO-d₆) δ: 2.55 (3H, s), 2.92 (2H, d, J=6.9 Hz), 3.51 (2H, m),7.39 (2H, d, J=8.7 Hz), 7.67 (2H, d, J=8.7 Hz), 7.75 (2H, d, J=8.7 Hz),7.89 (2H, d, J=8.7 Hz), 8.67 (1H, d, J=5.4 Hz).

REFERENCE EXAMPLE 204-bromo-N-{2-[4-(1-hydroxyethyl)phenyl]ethyl}benzamide

To a solution of N-[2-(4-acetylphenyl)ethyl]-4-bromobenzamide (9.79 g,28.3 mmol) obtained in Reference Example 19 in a mixed solvent ofmethanol (140 ml) and tetrahydrofuran (30 ml) was added sodiumborohydride (2.14 g, 56.6 mmol), and the mixture was stirred at roomtemperature for 3 hrs. The reaction mixture was concentrated underreduced pressure, and water was added to the residue. The mixture wasextracted with ethyl acetate, and the extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure, and the obtained residue waspurified by alumina column chromatography (developing solvent; ethylacetate), and powderized with isopropyl ether to give the title compound(8.76 g).

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, d, J=6.6 Hz), 2.81 (2H, m), 3.45 (2H, m),4.67 (1H, m), 5.07 (1H, m), 7.17 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.4Hz), 7.68 (2H, d, J=8.7 Hz), 7.77 (2H, d, J=8.7 Hz), 8.66 (1H, d, J=5.4Hz).

REFERENCE EXAMPLE 214-bromo-N-{2-[4-(1-chloroethyl)phenyl]ethyl}benzamide

A solution of 4-bromo-N-{2-[4-(1-hydroxyethyl)phenyl]ethyl}benzamide(1.65 g, 4.74 mmol) obtained in Reference Example 20 in thionyl chloride(24 ml) was stirred at room temperature for 1 hr, and the reactionmixture was concentrated under reduced pressure. Ethyl acetate was addedto the residue, and the mixture was washed with aqueous potassiumhydrogencarbonate solution and saturated brine, and dried over anhydroussodium sulfate. The solvent was concentrated under reduced pressure, andthe obtained residue was purified by alumina column chromatography(developing solvent; ethyl acetate), and powderized with isopropyl etherto give the title compound (1.52 g).

¹H-NMR (DMSO-d₆) δ: 1.77 (3H, d, J=6.9 Hz), 2.84 (2H, m), 3.47 (2H, m),5.32 (1H, m), 7.24 (2H, d, J=8.1 Hz), 7.40 (2H, d, J=8.1 Hz), 7.68 (2H,d, J=8.7 Hz), 7.77 (2H, d, J=8.7 Hz), 8.68 (1H, d, J=5.4 Hz).

REFERENCE EXAMPLE 224′-chloro-N-[2-(4-methoxyphenyl)ethyl][1,1′-biphenyl]-4-carboxamide

To a solution of 2-(4-methoxyphenyl)ethaneamine (500 mg, 3.31 mmol),4′-chloro[1,1′-biphenyl]-4-carboxylic acid (846 mg, 3.64 mmol) and1-hydroxybenzotriazole (760 mg, 4.96 mmol) in dimethylformamide (10 ml)was added ethyldimethylaminopropylcarbodiimide hydrochloride (951 mg,4.96 mmol) at 0° C., and the mixture was was stirred at room temperaturefor 16 hrs. Ethyl acetate was added to the reaction mixture, and themixture was washed with 1N aqueous sodium hydroxide solution and brine,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure to give the title compound (1.03 g).

¹H-NMR (CDCl₃) δ: 2.89 (2H, t, J=6.8 Hz), 3.71 (2H, m), 3.80 (3H, s),6.13 (1H, t, J=5.3 Hz), 6.87 (2H, d, J=9.1 Hz), 7.16 (2H, d, J=9.1 Hz),7.41 (2H, d, J=8.9 Hz), 7.51 (2H, d, J=8.9 Hz), 7.58 (2H, d, J=8.6 Hz),7.75 (2H, d, J=8.6 Hz).

REFERENCE EXAMPLE 234-bromo-N-{2-[4-(4-chlorobutanoyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in ReferenceExample 19 and using 4-bromo-N-(2-phenylethyl)benzamide and4-chlorobutyryl chloride.

¹H NMR (DMSO-d₆) δ2.06 (2H, m), 2.92 (2H, m), 3.15 (2H, m), 3.52 (2H,m), 3.71 (2H, m), 7.39 (2H, d, J=8.4 Hz), 7.67 (2H, d, J=8.8 Hz), 7.76(2H, d, J=8.8 Hz), 7.90 (2H, d, J=8.4 Hz), 8.66 (1H, m).

REFERENCE EXAMPLE 244-bromo-N-{2-[4-(cyclopropylcarbonyl)phenyl]ethyl}benzamide

A solution of 4-bromo-N-{2-[4-(4-chlorobutanoyl)phenyl]ethyl}benzamide(4.10 g, 10.0 mmol) obtained in Reference Example 23 and 85% potassiumhydroxide (993 mg, 15.0 mmol) in tetrahydrofuran (60 ml)-methanol(60 ml)was stirred at room temperature for 1 hr. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure, and theobtained residue was purified by alumina column chromatography(developing solvent; ethyl acetate), and powderized with ethylacetate-isopropyl ether (1:5) to give the title compound (3.38 g).

¹H NMR (DMSO-d₆) δ1.01 (4H, m), 2.85-2.96 (3H, m), 3.52 (2H, m), 7.39(2H, d, J=8.1 Hz), 7.66 (2H, d, J=8.4 Hz), 7.74 (2H, d, J=8.4 Hz), 7.97(2H, d, J=8.1 Hz), 8.65 (1H, t, J=6.0 Hz).

REFERENCE EXAMPLE 25 2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethylamine

A solution of4-bromo-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}benzamide (1.12 g,2.89 mmol) obtained in Example 136 in concentrated hydrochloric acid (14ml) was stirred at 100° C. for one day. Water was added to the reactionmixture, and the mixture was washed with diethyl ether and basified withpotassium carbonate. This was extracted with ethyl acetate, and theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure, and theobtained residue was purified by alumina column chromatography(developing solvent; ethyl acetate:methanol=1:1) to give the titlecompound (305 mg).

¹H NMR (CDCl₃) δ1.75-1.83 (2H, m), 1.93-2.05 (1H, m) 2.11-2.31 (5H, m),2.74 (2H, m), 2.95-3.03 (3H, m), 3.24 (1H, m), 7.15 (2H, d, J=8.1 Hz),7.27 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 26N-methyl-2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine

To a solution of 2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine (9.26g, 31.8 mmol) obtained in Reference Example 14 and triethylamine (15.5ml, 111 mmol) in tetrahydrofuran (200 ml) was added dropwise methylchlorocarbonate (2.46 ml, 31.8. mmol) at 0° C., and the mixture wasstirred at room temperature for 3 hrs. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure, and theobtained pale-yellow solid was dissolved in tetrahydrofuran (200 ml).Lithium aluminum hydride (1.21 g, 32.0 mmol) was added at 0° C., and themixture was heated under reflux for 3 hrs. The reaction mixture wascooled to 0° C. and water was added. The mixture was extracted withethyl acetate, and the extract was washed with saturated brine, anddried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure, and the obtained residue was purified by NH-silica gelcolumn chromatography (developing solvent; ethyl acetate) to give thetitle compound (4.05 g).

¹H NMR (CDCl₃) δ1.38 (3H, d, J=6.6 Hz), 1.75 (4H, m) 2.34 (2H, m), 2.44(3H, s), 2.55 (2H, m), 2.77 (4H, m), 3.15 (1H, q, J=6.6 Hz), 7.13 (2H,d, J=8.0 Hz), 7.25 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 27(E)-N-(4-bromophenyl)-3-(4-formylphenyl)-2-propenamide

The title compound was obtained by a similar operation as in Example 2and using (E)-3-(4-formylphenyl)-2-propenoic acid.

¹H-NMR (DMSO-d₆) δ: 6.95 (1H, d, J=15.9 Hz), 7.53 (2H, d, J=9.0 Hz),7.66 (3H, m), 7.84 (2H, d, J=8.4 Hz), 7.97 (2H, d, J=8.4 Hz), 10.02 (1H,s), 10.45 (1H, s).

REFERENCE EXAMPLE 28 4-(1-pyrrolidinylmethyl)benzoic acid hydrochloride

A solution of methyl 4-(1-pyrrolidinylmethyl)benzoate hydrochloride(3.18 g, 12.4 mmol) in 6N hydrochloric acid (30 ml) was stirred at 100°C. for 16 hrs. The solvent was evaporated under reduced pressure, andthe residue was powderized with tetrahydrofuran to give the titlecompound (1.74 g).

¹H-NMR (CD₃OD) δ: 2.11 (4H, m), 3.40 (4H, m), 4.47 (2H, s), 7.65 (2H, d,J=8.8 Hz), 8.12 (2H, d, J=8.8 Hz).

REFERENCE EXAMPLE 29N-(4-bromophenyl)-2-[4-(hydroxymethyl)phenoxy]acetamide

The title compound was obtained by a similar operation as in Example 2and using 4-bromoaniline and [4-(hydroxymethyl)phenoxy]acetic acid.

¹H-NMR (DMSO-d₆) δ: 4.41 (2H, d, J=5.7 Hz), 4.67 (2H, s), 5.06 (1H, t,J=5.7 Hz), 6.94 (2H, d, J=8.7 Hz), 7.24 (2H, d, J=8.7 Hz), 7.49 (2H, d,J=8.7 Hz), 7.62 (2H, d, J=8.7 Hz), 10.19 (1H, s).

REFERENCE EXAMPLE 30 4-(1-pyrrolidinylmethyl)benzaldehyde

To a solution of 4-(dimethoxymethyl)benzaldehyde (25.0 g, 120 mmol),pyrrolidine (10.0 ml, 120 mmol), acetic acid (6.87 ml, 120 mmol) andanhydrous sodium sulfate (34.1 g, 240 mmol) in dichloromethane (300 ml)was added sodium triacetoxyborohydride (38.2 g, 180 mmol), and themixture was stirred for 3 days. Potassium carbonate was added to thereaction mixture, and the solvent was evaporated under reduced pressure.Ethyl acetate was added to the residue, and the mixture was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby alumina column chromatography (developing solvent; ethyl acetate). 1NHydrochloric acid (300 ml) was added to the obtained oil, and themixture was washed with diethyl ether after 2 hrs. The aqueous layer wasbasified with potassium carbonate, and extracted with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was purified by alumina column chromatography(developing solvent; ethyl acetate) to give the title compound (22.7 g).

¹H-NMR (CDCl₃) δ: 1.80 (4H, m), 2.52 (4H, m), 3.68. (2H, s), 7.50 (2H,d, J=8.1 Hz), 7.82 (2H, d, J=8.1 Hz), 9.98 (1H, s).

REFERENCE EXAMPLE 31(E)-2-phenyl-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenoic acidhydrochloride

Triethyl phosphite (8.58 ml, 50 mmol) was added to ethylbromo(phenyl)acetate (9.73 g, 40.0 mmol), and the mixture was stirred at160° C. for 1 hr. Triethyl phosphate (8.58 ml, 50 mmol) was furtheradded, and the mixture was stirred for 1 hr. Excess triethyl phosphitewas evaporated under reduced pressure, and the residue was dissolved intetrahydrofuran (100 ml). This solution was added dropwise to a solutionof 60% sodium hydride (1.60 g, 40.0 mmol) in tetrahydrofuran (50 ml) at0° C. After stirring for 10 min., a solution of4-(1-pyrrolidinylmethyl)benzaldehyde (7.58 g, 40.0 mmol) obtained inReference Example 30 in tetrahydrofuran (50 ml) was added dropwise, andthe mixture was stirred at room temperature for 1 hr. The solvent wasevaporated under reduced pressure, and isopropyl ether was added to theresidue. The mixture was washed with saturated brine, and extracted with1N hydrochloric acid. The aqueous layer was washed with isopropyl ether,and the aqueous layer was basified with potassium carbonate, andextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby alumina column chromatography (developing solvent; ethyl acetate) togive an oil (10.3 g). A solution of the obtained oil (1.00 g, 2.98 mmol)in concentrated hydrochloric acid (15 ml) was stirred at 100° C. for oneday and concentrated under reduced pressure. The obtained residue waswashed with acetonitrile and tetrahydrofuran to give the title compound(150 mg).

¹H-NMR (DMSO-d₆) δ: 1.85 (2H, m), 1.97 (2H, m), 2.98 (2H, m), 3.33 (2H,m), 4.23 (2H, s), 7.09 (2H, d, J=8.1 Hz), 7.16 (2H, m), 7.38 (5H, m),7.76 (1H, s), 10.72 (1H, br).

REFERENCE EXAMPLE 32(4-chlorophenyl)[4-(1-pyrrolidinylmethyl)phenyl]methanone

Acetonitrile (55 ml) was added to[4-(bromomethyl)phenyl](4-chlorophenyl)methanone (6.71 g, 21.7 mmol),potassium carbonate (5.99 g, 43.3 mmol) and pyrrolidine (3.62 ml, 43.3mmol), and the mixture was stirred at 80° C. for 16 hrs. The solvent wasconcentrated, and diethyl ether was added to the residue. The mixturewas extracted with 1N hydrochloric acid. The extract was basified withpotassium carbonate, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, and the solvent wasevaporated under reduced pressure. The obtained residue was purified byalumina column chromatography (developing solvent; ethyl acetate). togive the title compound (4.79 g).

¹H-NMR (DMSO-d₆) δ: 1.71 (4H, m), 2.46 (4H, m), 3.67 (2H, s), 7.49 (2H,d, J=8.1 Hz), 7.62 (2H, d, J=8.4 Hz), 7.69 (2H, d, J=8.1 Hz), 7.74 (2H,d, J=8.4 Hz).

REFERENCE EXAMPLE 33(Z)-3-(4-chlorophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenoicacid hydrochloride

To a solution of (4-chlorophenyl)[4-(1-pyrrolidinylmethyl)phenyl]methanone (1.00 g, 3.34 mmol) obtainedin Reference Example 32 and tert-butyl (diethoxyphosphoryl)acetate (1.18ml, 5.00 mmol) in tetrahydrofuran (17 ml) was added 60% sodium hydride(200 mg, 5.00 mmol) at 0° C., and the mixture was stirred at roomtemperature for 4 hrs. Ethyl acetate was added to the reaction mixture,and the mixture was washed with aqueous potassium carbonate solution andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue waspurified by alumina column chromatography (developing solvent; ethylacetate) to give an oil (10.3 g). A solution of the obtained oil (1.33g, 3.34 mmol) in 4N hydrogen chloride-ethyl acetate (17 ml) was stirredat room temperature for one day, and concentrated under reducedpressure. The obtained residue was washed with isopropanol andacetonitrile to give the title compound (425 mg).

¹H-NMR (DMSO-d₆) δ: 1.88 (2H, m), 1.99 (2H, m), 3.05 (2H, m), 3.34 (2H,m), 4.34 (2H, d, J=5.7 Hz), 6.45 (1H, s), 7.16 (2H, d, J=8.1 Hz), 7.34(2H, d, J=8.1 Hz), 7.45 (2H, d, J=8.1 Hz), 7.55 (2H, d, J=8.1 Hz), 10.37(1H, br).

REFERENCE EXAMPLE 34 2-(4-formylphenoxy)propionic acid

A solution of ethyl 2-bromopropanoate (6.38 ml, 49.1 mmol),4-hydroxybenzaldehyde (5.00 g, 40.9 mmol) and potassium carbonate (6.79g, 49.1 mmol) in acetonitrile (25 ml) was stirred at 60° C. for 16 hrs.Ethyl acetate was added to the reaction mixture, and the mixture waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the obtained residuewas purified by alumina column chromatography (developing solvent; ethylacetate) to give an oil. To a solution of the obtained oil (9.10 g, 40.9mmol) in ethanol (200 ml) was added 1N aqueous sodium hydroxide solution(61.4 ml), and the mixture was stirred at room temperature for 16 hrs,and concentrated under reduced pressure. Ethyl acetate was added to theobtained residue. The mixture was washed with 1N hydrochloric acid andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the obtained redsidue waspowderized with isopropyl ether to give the title compound (5.68 g).

¹H-NMR (DMSO-d₆) δ: 1.71 (3H, d, J=6.6 Hz), 4.91 (1H, q, J=6.6 Hz), 6.99(2H, d, J=8.4 Hz), 7.83 (2H, d, J=8.4 Hz), 9.87 (1H, s).

REFERENCE EXAMPLE 35 N-(4-bromophenyl)-2-(4-formylphenoxy)propanamide

The title compound was obtained by a similar operation as in Example 2and using 2-(4-formylphenoxy)propanoic acid obtained in ReferenceExample 34 and 4-bromoaniline.

¹H-NMR (DMSO-d₆) δ: 1.71 (3H, d, J=6.6 Hz), 4.91 (1H, q, J=6.6 Hz), 7.09(2H, d, J=8.8 Hz), 7.44 (4H, s-like), 7.89 (2H, d, J=8.8 Hz), 8.03 (1H,s), 9.92 (1H, s).

REFERENCE EXAMPLE 36N-(4-bromophenyl)-2-[4-(2-oxopropyl)phenoxy]propanamide

A solution of 2-bromo-N-(4-bromophenyl)propanamide (3.00 g, 10.2 mmol),1-(4-hydroxyphenyl)acetone (1.54 g, 10.2 mmol) and potassium carbonate(2.83 g, 20.5 mmol) in DMF (20 ml) was stirred at room temperature for 4hrs. Ethyl acetate was added to the reaction mixture, and the mixturewas washed with 1N aqueous sodium hydroxide solution and brine. Thesolvent was evaporated under reduced pressure, and the obtained crudecrystals were recrystallized from isopropyl ether-ethyl acetate to givethe title compound (2.75 g).

¹H-NMR (CDCl₃) δ: 2.17 (3H, s), 3.68 (2H, s), 4.60 (2H, s), 6.95 (2H,m), 7.18 (2H, m), 7.48 (4H, m), 8.24 (1H, s).

REFERENCE EXAMPLE 37N-(4′-chloro-1,1′-biphenyl-4-yl)-2-[4-(2-oxopropyl)phenoxy]propanamide

The title compound was obtained by a similar operation as in Example 6and using N-(4-bromophenyl)-2-[4-(2-oxopropyl)phenoxy]propanamideobtained in Reference Example 36 and 4-chlorophenylboronic acid.

¹H-NMR (CDCl₃) δ: 2.18 (3H, s), 3.68 (2H, s), 4.63 (2H, s), 6.98 (2H,m), 7.19 (2H, m), 7.40 (2H, m), 7.52 (4H, m), 7.67 (2H, m), 8.32 (1H,s).

REFERENCE EXAMPLE 38N-(4-bromobenzyl)-2-[4-(1-pyrrolidinylmethyl)phenyl]acetamide

To a solution of 4-bromobenzylamine hydrochloride (971 mg, 4.37 mmol),[4-(bromomethyl)phenyl]acetic acid (1.00 g, 4.37 mmol),1-hydroxybenzotriazole (590 mg, 4.37 mmol) and triethylamine (668 μl,4.80 mmol) in dimethylformamide (11 ml) was addedethyldimethylaminopropylcarbodiimide hydrochloride (837 mg, 4.37 mmol)at 0° C., and the mixture was stirred at room temperature 16 hrs. Ethylacetate was added to the reaction mixture. The mixture was washed withaqueous potassium carbonate solution and saturated brine and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure, and the obtained residue was purified by alumina columnchromatography (developing solvent; ethyl acetate), and powderized withethyl acetate-isopropyl ether (1:5). A solution of the obtained powder(850 mg, 2.24 mmol), pyrrolidine (561 μl, 6.37 mmol) and potassiumcarbonate (930 mg, 6.37 mmol) in dimethylformamide (10 ml) was stirredat 80° C. for 16 hrs. Ethyl acetate was added to the reaction mixture,and the mixture was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was concentrated under reduced pressure andthe obtained residue was purified by NH-silica gel column chromatography(developing solvent; ethyl acetate), and powderized with isopropyl etherto give the title compound (437 mg).

¹H-NMR (DMSO-d₆) δ: 1.68 (4H, m), 2.40 (4H, m), 3.44 (2H, s), 3.52 (2H,s), 4.21 (2H, d, J=6.0 Hz), 7.14-7.23 (3H, m), 7.46 (2H, d, J=8.7 Hz),8.53 (2H, t, J=6.0 Hz).

melting point: 107-109° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 387 [M+H]+

REFERENCE EXAMPLE 39N-[(4′-chloro-1,1′-biphenyl-4-yl)methyl]-2-[4-(1-pyrrolidinylmethyl)phenyl]acetamide

The title compound was obtained by a similar operation as in Example 6and using N-(4-bromobenzyl)-2-[4-(1-pyrrolidinylmethyl)phenyl]acetamideobtained in Reference Example 38 and 4-chlorophenylboronic acid.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.40 (4H, m), 3.46 (2H, s), 3.53 (2H,s), 4.29 (2H, d, J=5.7 Hz), 7.21 (4H, s-like), 7.30 (2H, d, J=9.0 Hz),7.49 (2H, d, J=9.0 Hz), 7.59 (2H, d, J=9.0 Hz), 7.66 (2H, d, J=9.0 Hz),8.55 (2H, t, J=6.0 Hz).

melting point: 151-153° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 419 [M+H]+

REFERENCE EXAMPLE 40N-(4-pentylphenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]propanamide

The title compound was obtained by similar operations as in Example 2and Reference Example 3 and using 3-[4-(methoxycarbonyl)phenyl]propionicacid obtained in Reference Example 1.

¹H-NMR (DMSO-d₆) δ: 0.85 (3H, t, J=6.9 Hz), 1.26 (4H, m), 1.53 (2H, m),1.66 (4H, m), 2.38 (4H, m), 2.49 (2H, m), 2.57 (2H, t, J=7.5 Hz), 2.87(2H, t, J=7.5 Hz), 3.50 (2H, s), 7.07 (2H, d, J=8.7 Hz), 7.18 (4H, m),7.44 (2H, d, J=8.7 Hz), 9.78 (1H, s).

melting point: 104-105° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 379 [M+H]+

REFERENCE EXAMPLE 41N-(4-bromophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]propanamide

The title compound was obtained by similar operations as in Example 2and Reference Example 3 and using 3-[4-(methoxycarbonyl)phenyl]propionicacid obtained in Reference Example 1.

¹H-NMR (DMSO-d₆) δ: 1.66 (4H, m), 2.38 (4H, m), 2.60 (2H, t, J=7.5 Hz),2.88 (2H, t, J=7.5 Hz), 3.50 (2H, s), 7.18 (4H, m), 7.45 (2H, d, J=9.0Hz), 7.54 (2H, d, J=9.0 Hz), 10.01 (1H, s).

melting point: 137-138° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 387 [M+H]+

REFERENCE EXAMPLE 42N-(4′-chloro-1,1′-biphenyl-4-yl)-3-[4-(1-pyrrolidinylmethyl)phenyl]propanamide

The title compound was obtained by a similar operation as in Example 6and usingN-(4-bromophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]propanamide obtainedin Reference Example 41.

¹H-NMR (DMSO-d₆) δ: 1.66 (4H, m), 2.38 (4H, m), 2.63 (2H, t, J=7.5 Hz),2.90 (2H, t, J=7.5 Hz), 3.50 (2H, s), 7.19 (4H, m), 7.47 (2H, d, J=8.4Hz), 7.59-7.68 (6H, m), 10.00 (1H, s).

melting point: 179-181° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 419 [M+H]+

REFERENCE EXAMPLE 43(E)-N-(4-bromophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamide

To a solution of (E)-N-(4-bromophenyl)-3-(4-formylphenyl)-2-propenamide(400 mg, 1.21 mmol) obtained in Reference Example 27 and pyrrolidine(303 μl, 3.63 mmol) in acetic acid-methanol-tetrahydrofuran (3 ml×3) wasadded sodium triacetoxyborohydride (770 mg, 3.63 mmol), and the mixturewas stirred at room temperature for 2 days. Ethyl acetate was added tothe reaction mixture, and the mixture was washed with saturated aqueouspotassium carbonate solution and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the obtained residue was purified by NH-silica gel columnchromatography (developing solvent; ethyl acetate:hexane=1:1), andpowderized with hexane to give the title compound (123 mg).

¹H-NMR (DMSO-d₆) δ: 1.70 (4H, m), 2.46 (4H, m), 3.62 (2H, s), 6.78 (1H,d, J=15.6 Hz), 7.37 (2H, d, J=8.1 Hz), 7.49-7.60 (5H, m), 7.67 (2H, d,J=8.7 Hz), 10.31 (1H, s)

melting point: 184-186° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 385 [M+H]+

REFERENCE EXAMPLE 44(E)-N-(4′-chloro-1,1′-biphenyl-4-yl)-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamide

The title compound was obtained by a similar operation as in Example 6and using(E)-N-(4-bromophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamideobtained in Reference Example 43.

¹H-NMR (DMSO-d₆) δ: 1.71 (4H, m), 2.45 (4H, m), 3.61 (2H, s), 6.83 (1H,d, J=15.3 Hz), 7.38 (2H, d, J=8.1 Hz), 7.49 (2H, d, J=8.1 Hz), 7.59 (3H,m), 7.67 (4H, m), 7.80 (2H, d, J=8.7 Hz), 10.32 (1H, s).

melting point: 207-209° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 417 [M+H]+

REFERENCE EXAMPLE 45N-[2-(4′-chloro-1,1′-biphenyl-4-yl)ethyl]-4-(1-pyrrolidinylmethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 4-(1-pyrrolidinylmethyl)benzoic acid hydrochloride obtained inReference Example 28.

¹H-NMR (DMSO-d₆) δ: 1.69 (4H, m), 2.43 (4H, m), 2.89 (2H, t, J=7.0 Hz),3.50 (2H, m), 3.61 (2H, s), 7.36 (4H, m), 7.50 (2H, d, J=8.8 Hz), 7.61(2H, d, J=8.4 Hz), 7.68 (2H, d, J=8.4 Hz), 7.78 (2H, d, J=8.0 Hz), 8.57(1H, t, J=7.8 Hz).

melting point: 187-189° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 419 [M+H]+

REFERENCE EXAMPLE 46N-(4-bromophenyl)-2-[4-(1-pyrrolidinylmethyl)phenoxy]acetamide

To a solution (15 ml) ofN-(4-bromophenyl)-2-[4-(hydroxymethyl)phenoxy]acetamide (1.00 g, 2.97mmol) obtained in Reference Example 29 and triethylamine (0.496 ml, 3.57mmol) in dimethylformamide was added methanesulfonyl chloride (0.253 ml,3.27 mmol) at 0° C., and the mixture was stirred for 1 hr. Pyrrolidine(0.745 ml, 8.92 mmol) and potassium carbonate (1.23 g, 8.92 mmol) wereadded, and the mixture was stirred at 60° C. for 16 hrs. 1N Hydrochloricacid was added to the reaction mixture and the mixture was washed withdiethyl ether. The aqueous layer was basified with potassium carbonateand extracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby alumina column chromatography (developing solvent; ethyl acetate),and powderized with diisopropyl ether to give the title compound (484mg).

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.38 (4H, m), 3.48 (2H, s), 4.67 (2H,s), 6.92 (2H, d, J=8.7 Hz), 7.21 (2H, d, J=8.7 Hz), 7.50 (2H, d, J=8.7Hz), 7.62 (2H, d, J=8.7 Hz), 10.19 (1H, s).

melting point: 143-145° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 389 [M+H]+

REFERENCE EXAMPLE 47N-(4′-chloro-1,1′-biphenyl-4-yl)-2-[4-(1-pyrrolidinylmethyl)phenoxy]acetamide

The title compound was obtained by a similar operation as in Example 6and using N-(4-bromophenyl)-2-[4-(1-pyrrolidinylmethyl)phenoxy]acetamideobtained in Reference Example 46.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.40 (4H, m), 3.50 (2H, s), 4.69 (2H,s), 6.94 (2H, d, J=8.7 Hz), 7.23 (2H, d, J=8.7 Hz), 7.48 (2H, d, J=8.7Hz), 7.65 (4H, m), 7.74 (2H, d, J=8.7 Hz), 10.18 (1H, s).

melting point: 167-169° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 421 [M+H]+

REFERENCE EXAMPLE 48(E)-N-(4-bromophenyl)-2-phenyl-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamide

The title compound was obtained by a similar operation as in Example 2and using (E)-2-phenyl-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenoicacid hydrochloride obtained in Reference Example 31.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.38 (4H, m), 3.50 (2H, s), 7.01 (2H,d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.23 (2H, m), 7.38 (4H, m), 7.49(2H, d, J=8.7 Hz), 7.66 (2H, d, J=8.7 Hz), 10.07 (1H, s).

melting point: 158-160° C. (ethyl acetate-hexane)

FABMS (pos) 461 [M+H]+

REFERENCE EXAMPLE 49(E)-N-(4′-chloro-1,1′-biphenyl-4-yl)-2-phenyl-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamide

The title compound was obtained by a similar operation as in Example 6and using(E)-N-(4-bromophenyl)-2-phenyl-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamideobtained in Reference Example 48.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.39 (4H, m), 3.51 (2H, s), 7.02 (2H,d, J=8.0 Hz), 7.13 (2H, d, J=8.0 Hz), 7.27 (2H, m), 7.39 (4H, m), 7.49(2H, d, J=8.8 Hz), 7.67 (4H, m), 7.80 (2H, d, J=8.8 Hz), 10.05 (1H, s).

melting point: 146-147° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 493 [M+H]+

REFERENCE EXAMPLE 50N-(4-bromo-2-fluorophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]propanamide

The title compound was obtained by similar operations as in Example 2and Reference Example 3 and using 3-[4-(methoxycarbonyl)phenyl]propionicacid obtained in Reference Example 1.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.38 (4H, m), 2.68 (2H, m), 2.87 (2H,m), 3.50 (2H, s), 7.17 (4H, m), 7.35 (1H, m), 7.55 (1H, dd, J=2.1, 10.5Hz), 7.85 (1H, m), 9.76 (1H, s).

melting point: 101-102° C. (ethyl acetate-hexane)

FABMS (pos) 405 [M+H]+

REFERENCE EXAMPLE 51N-(4′-chloro-3-fluoro-1,1′-biphenyl-4-yl)-3-[4-(1-pyrrolidinylmethyl)phenyl]propanamide

The title compound was obtained by a similar operation as in Example 6and usingN-(4-bromo-2-fluorophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]propanamideobtained in Example 50.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.40 (4H, m), 2.71 (2H, m), 2.90 (2H,m), 3.52 (2H, s), 7.20 (4H, m), 7.52 (3H, m), 7.57-7.63 (1H, m), 7.72(2H, d, J=8.8 Hz), 8.00 (1H, m), 9.78 (1H, s).

melting point: 141-143° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 437 [M+H]+

REFERENCE EXAMPLE 52N-(4-bromo-2-fluorophenyl)-2-[4-(1-pyrrolidinylmethyl)phenoxy]acetamide

The title compound was obtained by similar operations as in Example 2and Reference Example 46 and using 4-(hydroxymethyl)phenoxyacetic acid.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.40 (4H, m), 3.49 (2H, s), 4.73 (2H,s), 6.91 (2H, d, J=8.7 Hz), 7.22 (2H, d, J=8.7 Hz), 7.39 (1H, m), 7.62(1H, dd, J=2.4, 10.5 Hz), 7.79 (1H, m), 9.93 (1H, s).

melting point: 102-103° C. (ethyl acetate-hexane)

FABMS (pos) 407 [M+H]+

REFERENCE EXAMPLE 53N-(4′-chloro-3-fluoro-1,1′-biphenyl-4-yl)-2-[4-(1-pyrrolidinylmethyl)phenoxy]acetamide

The title compound was obtained by a similar operation as in Example 6and usingN-(4-bromo-2-fluorophenyl)-2-[4-(1-pyrrolidinylmethyl)phenoxy]acetamideobtained in Example 52.

¹H-NMR (DMSO-d₆) δ: 1.68 (4H, m), 2.41 (4H, m), 3.51 (2H, s), 4.77 (2H,s), 6.94 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.52 (3H, m), 7.65(1H, m), 7.74 (2H, d, J=8.8 Hz), 7.95 (1H, m), 9.94 (1H, s).

melting point: 121-123° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 439 [M+H]+

REFERENCE EXAMPLE 54(Z)-N-(4-bromophenyl)-3-(4-chlorophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamide

The title compound was obtained by a similar operation as in Example 2and using(Z)-3-(4-chlorophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenoicacid hydrochloride obtained in Reference Example 33.

¹H-NMR (DMSO-d₆) δ: 1.69 (4H, m), 2.43 (4H, m), 3.59 (2H, s), 6.64 (1H,s), 7.17 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.4Hz), 7.41 (2H, d, J=8.4 Hz), 7.43 (2H, d, J=8.4 Hz), 7.50 (2H, d, J=8.4Hz), 10.26 (1H, s).

melting point: 144-146° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 495 [M+H]+

REFERENCE EXAMPLE 55(Z)-N-(4′-chloro-1,1′-biphenyl-4-yl)-3-(4-chlorophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamide

The title compound was obtained by a similar operation as in Example 6and using(Z)-N-(4-bromophenyl)-3-(4-chlorophenyl)-3-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamideobtained in Reference Example 54.

¹H-NMR (DMSO-d₆) δ: 1.69 (4H, m), 2.43 (4H, m), 3.58 (2H, s), 6.68 (1H,s), 7.21 (4H, m), 7.33 (2H, d, J=8.1 Hz), 7.42 (2H, d, J=8.4 Hz), 7.47(2H, d, J=8.4 Hz), 7.62 (6H, m), 10.25 (1H, s).

melting point: 178-180° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 527 [M+H]+

REFERENCE EXAMPLE 563-(4-bromophenyl)-N-[4-(1-pyrrolidinylmethyl)phenyl]propanamide

The title compound was obtained by a similar operation as in Example 2and using 3-(4-bromophenyl)propanoic acid and4-(1-pyrrolidinylmethyl)aniline.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.38 (4H, m), 2.59 (2H, d, J=7.8 Hz),2.87 (2H, d, J=7.8 Hz), 3.48 (2H, s), 7.19 (4H, m), 7.45 (2H, d, J=8.1Hz), 7.48 (2H, d, J=8.7 Hz), 9.84 (1H, s).

melting point: 132-134° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 387 [M+H]+

REFERENCE EXAMPLE 573-(4′-chloro-1,1′-biphenyl-4-yl)-N-[4-(1-pyrrolidinylmethyl)phenyl]propanamide

The title compound was obtained by a similar operation as in Example 6and using3-(4-bromophenyl)-N-[4-(1-pyrrolidinylmethyl)phenyl]propanamide obtainedin Reference Example 56.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.39 (4H, m), 2.65 (2H, m), 2.95 (2H,m), 3.49 (2H, s), 7.20 (1H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.49(2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.67(2H, d, J=8.4 Hz), 9.89 (1H, s).

melting point: 173-175° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 419 [M+H]+

REFERENCE EXAMPLE 58(E)-3-(4-bromophenyl)-N-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamide

The title compound was obtained by a similar operation as in Example 2and using (E)-3-(4-bromophenyl)-2-propenoic acid and4-(1-pyrrolidinylmethyl)aniline.

¹H-NMR (DMSO-d₆) δ: 1.68 (4H, m), 2.40 (4H, m), 3.51 (2H, s), 6.83 (1H,d, J=15.9 Hz), 7.24 (2H, d, J=8.4 Hz), 7.53 (1H, d, J=15.9 Hz),7.55-7.65 (6H, m), 10.17 (1H, s)

melting point: 183-185° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 385 [M+H]+

REFERENCE EXAMPLE 59(E)-3-(4′-chloro-1,1′-biphenyl-4-yl)-N-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamide

The title compound was obtained by a similar operation as in Example 6and using(E)-3-(4-bromophenyl)-N-[4-(1-pyrrolidinylmethyl)phenyl]-2-propenamideobtained in Reference Example 58.

¹H-NMR (DMSO-d₆) δ: 1.69 (4H, m), 2.42 (4H, m), 3.53 (2H, s), 6.88 (1H,d, J=15.6 Hz), 7.25 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz), 7.61 (1H,d, J=15.6 Hz), 7.64 (2H, d, J=8.4 Hz), 7.69-7.78 (8H, m), 10.17 (1H, s).

melting point: 204-207° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 417 [M+H]+

REFERENCE EXAMPLE 602-(4-bromophenyl)-N-[4-(1-pyrrolidinylmethyl)benzyl]acetamide

The title compound was obtained by a similar operation as in Example 2and using 4-(1-pyrrolidinylmethyl)benzylamine and (4-bromophenyl)aceticacid.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.39 (4H, m), 3.45 (2H, s), 3.52 (2H,s), 4.23 (2H, d, J=6.0 Hz), 7.14 (2H, d, J=8.4 Hz), 7.22 (4H, m), 7.48(2H, d, J=8.4 Hz), 8.51 (1H, t, J=6.0 Hz).

melting point: 150-152° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 387 [M+H]+

REFERENCE EXAMPLE 612-(4′-chloro-1,1′-biphenyl-4-yl)-N-[4-(1-pyrrolidinylmethyl)benzyl]acetamide

The title compound was obtained by a similar operation as in Example 6and using 2-(4-bromophenyl)-N-[4-(1-pyrrolidinylmethyl)benzyl]acetamideobtained in Reference Example 60.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.39 (4H, m), 3.52 (4H, m), 4.25 (2H,d, J=6.0 Hz), 7.20 (4H, m), 7.37 (2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.4Hz), 7.61 (2H, d, J=8.4 Hz), 7.68 (2H, d, J=8.4 Hz), 8.55 (1H, t, J=6.0Hz).

melting point: 174-176° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 419 [M+H]+

REFERENCE EXAMPLE 62N-(4-bromophenyl)-2-[4-(1-pyrrolidinylmethyl)phenoxy]propanamide

The title compound was obtained by a similar operation as in ReferenceExample 43 and using N-(4-bromophenyl)-2-(4-formylphenoxy)propanamide inobtained Reference Example 35 and pyrrolidine.

¹H-NMR (DMSO-d₆) δ: 1.53 (3H, d, J=6.6 Hz), 1.66 (4H, m), 2.37 (4H, m),3.46 (2H, s), 4.82 (1H, q, J=6.6 Hz), 6.88 (2H, d, J=8.7 Hz), 7.19 (2H,d, J=8.7 Hz), 7.47 (2H, d, J=8.7 Hz), 7.59 (2H, d, J=8.7 Hz), 10.21 (1H,s).

melting point: 116-118° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 403 [M+H]+

REFERENCE EXAMPLE 63N-(4′-chloro-1,1′-biphenyl-4-yl)-2-[4-(1-pyrrolidinylmethyl)phenoxy]propanamide

The title compound was obtained by a similar operation as in Example 6and usingN-(4-bromophenyl)-2-[4-(1-pyrrolidinylmethyl)phenoxy]propanamideobtained in Reference Example 62.

¹H-NMR (DMSO-d₆) δ: 1.55 (3H, d, J=6.6 Hz), 1.66 (4H, m), 2.39 (4H, m),3.48 (2H, s), 4.86 (1H, q, J=6.6 Hz), 6.91 (2H, d, J=8.7 Hz), 7.21 (2H,d, J=8.7 Hz), 7.49 (2H, d, J=8.7 Hz), 7.63 (2H, d, J=8.7 Hz), 7.67 (2H,d, J=8.7 Hz), 7.74 (2H, d, J=8.7 Hz), 10.23 (1H, s).

melting point: 123-125° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 435 [M+H]+

REFERENCE EXAMPLE 644-bromo-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}benzenesulfonamide

To a solution of 2-[4-(1-piperidinylmethyl)phenyl]ethylaminedihydrochloride (300 mg, 1.03 mmol) obtained in Reference Example 6 andtriethylamine (0.473 ml, 3.40 mmol) in tetrahydrofuran (5 ml) was added4-bromobenzenesulfonyl chloride (290 mg, 1.13 mmol), and the mixture wasstirred at room temperature for 4 hrs. Ethyl acetate was added to thereaction mixture. The mixture was washed with aqueous potassiumcarbonate solution and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was purified by NH silica gel column chromatography(developing solvent; ethyl acetate), and powderized with hexane to givethe title compound (404 mg).

¹H-NMR (DMSO-d₆) δ: 1.38 (2H, m), 1.47 (4H, m), 2.28 (4H, m), 2.65 (2H,m), 2.97 (2H, m), 3.36 (2H, s), 7.08 (2H, d, J=8.1 Hz), 7.16 (2H, d,J=8.1 Hz), 7.68 (2H, d, J=8.4 Hz), 7.79 (2H, d, J=8.4 Hz), 7.83 (1H, m)

melting point: 109-110° C. (ethyl acetate-hexane)

REFERENCE EXAMPLE 654′-chloro-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-sulfonamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}benzenesulfonamideobtained in Reference Example 64.

¹H-NMR (DMSO-d₆) δ: 1.37 (2H, m), 1.45 (4H, m), 2.27 (4H, m), 2.67 (2H,m), 2.97 (2H, m), 3.33 (2H, s), 7.08 (2H, d, J=8.1 Hz), 7.15 (2H, d,J=8.1 Hz), 7.56 (2H, d, J=8.7 Hz), 7.74-7.88 (7H, m).

melting point: 136-138° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 66N-(4′-chloro-1,1′-biphenyl-4-yl)-2-{4-[2-(1-pyrrolidinyl)propyl]phenoxy}acetamide

The title compound was obtained by a similar operation as in ReferenceExample 43 and usingN-(4′-chloro-1,1′-biphenyl-4-yl)-2-[4-(2-oxopropyl)phenoxy]acetamideobtained in Reference Example 37 and pyrrolidine.

¹H-NMR (CDCl₃) δ: 0.98 (3H, d, J=6.1Hz), 1.81 (4H, m) 2.47 (2H, m), 2.67(4H, m), 3.08 (1H, dd, J=12.5, 3.2Hz), 4.61 (2H, s), 6.92 (2H, m), 7.15(2H, m), 7.39 (2H, m), 7.51 (4H, m), 7.66 (2H, m), 8.33 (1H, s),

melting point: 176-177° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 67N-(4′-chloro-1,1′-biphenyl-4-yl)-2-[2-methoxy-4-(1-pyrrolidinylmethyl)phenoxy]acetamide

To 4-hydroxy-3-methoxybenzaldehyde (2.02 g, 13.3 mmol),2-bromo-N-(4-bromophenyl)acetamide (3.00 g, 10.2 mmol) and potassiumcarbonate (2.12 g, 15.4 mmol) was added propionitrile (10 ml), and themixture was stirred at 80° C. for one day. The reaction mixture wasdiluted with ethyl acetate, washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the obtained residue was purified by alumina columnchromatography (developing solvent; ethyl acetate), and powderized withethyl acetate-diisopropyl ether (1:5) to give a phenoxyacetamidederivative (2.93 g). The title compound was obtained by similaroperations as in Reference Example 43 and Example 6 and using thiscompound.

¹H-NMR (DMSO-d₆) δ: 1.68 (4H, m), 2.41 (4H, m), 3.49 (2H, s), 3.81 (3H,s), 4.67 (2H, s), 6.79 (1H, dd, J=7.8, 2.1 Hz), 6.91 (1H, d, J=7.8 Hz),6.94 (1H, d, J=2.1 Hz), 7.50 (2H, d, J=8.7 Hz), 7.64-7.76 (6H, m), 10.16(1H, s).

melting point: 89-91° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 68N-(4′-chloro-1,1′-biphenyl-4-yl)-2-[2-chloro-4-(1-pyrrolidinylmethyl)phenoxy]acetamide

The title compound was obtained by a similar operation as in ReferenceExample 67 and using 3-chloro-4-hydroxybenzaldehyde.

¹H-NMR (DMSO-d₆) δ: 1.68 (4H, m), 2.41 (4H, m), 3.51 (2H, s), 4.83 (2H,s), 7.02 (1H, s, J=8.4 Hz), 7.20 (1H, dd, J=8.4, 1.8 Hz), 7.36 (1H, d,J=1.8 Hz), 7.49 (2H, d, J=8.4 Hz), 7.68 (6H, m), 10.25 (1H, s).

melting point: 121-123° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 69N-(4′-chloro-1,1′-biphenyl-4-yl)-2-[3-chloro-4-(1-pyrrolidinylmethyl)phenoxy]acetamide

The title compound was obtained by a similar operation as in ReferenceExample 67 and using 2-chloro-4-hydroxybenzaldehyde.

¹H-NMR (DMSO-d₆) δ: 1.69 (4H, m), 2.46 (4H, m), 3.60 (2H, s), 3.76 (2H,s), 6.98 (1H, dd, J=8.7, 2.4 Hz), 7.10 (1H, d, J=2.4 Hz), 7.40 (1H, d,J=8.7 Hz), 7.50 (2H, d, J=8.7 Hz), 7.65-7.76 (6H, m), 10.21 (1H, s).

melting point: 136-138° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 70N-(4′-chloro-1,1′-biphenyl-4-yl)-2-[2-fluoro-4-(1-pyrrolidinylmethyl)phenoxy]acetamide

The title compound was obtained by a similar operation as in ReferenceExample 67 and using 3-fluoro-4-hydroxybenzaldehyde.

¹H-NMR (DMSO-d₆) δ: 1.68 (4H, m), 2.40 (4H, m), 3.50 (2H, s), 4.80 (2H,s), 7.05 (2H, m), 7.16 (1H, d, J=11.4 Hz), 7.49 (1H, d, J=8.7 Hz),7.64-7.74 (6H, m), 10.28 (1H, s).

melting point: 158-160° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 71N-(4′-chloro-1,1′-biphenyl-4-yl)-2-[3-methoxy-4-(1-pyrrolidinylmethyl)phenoxy]acetamide

The title compound was obtained by a similar operation as in ReferenceExample 67 and using 4-hydroxy-2-methoxybenzaldehyde.

¹H-NMR (DMSO-d₆) δ: 1.66 (4H, m), 2.41 (4H, m), 3.49 (2H, s), 3.77 (3H,s), 4.71 (2H, s), 6.53 (1H, dd, J=8.1, 2.4 Hz), 6.66 (1H, d, J=2.4 Hz),7.19 (1H, d, J=8.1 Hz), 7.50 (2H, d, J=8.7 Hz), 7.65-7.70 (4H, m), 7.77(2H, d, J=8.7 Hz), 10.19 (1H, s).

melting point: 133-135° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 72N-(4′-chloro-1,1′-biphenyl-4-yl)-2-[2-methyl-4-(1-pyrrolidinylmethyl)phenoxy]acetamide

The title compound was obtained by a similar operation as in ReferenceExample 67 and using 4-hydroxy-3-methylbenzaldehyde.

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.24 (3H, s), 2.38 (4H, m), 3.46 (2H,s), 4.71 (2H, s), 6.81 (1H, d, J=8.7 Hz), 7.05 (1H, d, J=8.7 Hz), 7.10(1H, s), 7.49 (2H, d, J=8.7 Hz), 7.64-7.70 (4H, m), 7.74 (2H, d, J=8.7Hz), 10.17 (1H, s).

melting point: 142-144° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 73N-(4′-chloro-1,1′-biphenyl-4-yl)-2-{4-[1-(1-pyrrolidinyl)ethyl]phenoxy}acetamide

DMF (20 ml) was added to 1-(4-hydroxyphenyl)ethanone (1.81 g, 13.3mmol), 2-bromo-N-(4-bromophenyl)acetamide (3.00 g, 10.2 mmol), andpotassium carbonate (4.25 g, 30.7 mmol), and the mixture was stirred atroom temperature for 16 hrs. The reaction mixture was diluted with ethylacetate, washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theobtained residue was purified by alumina column chromatography(developing solvent; ethyl acetate), and powderized with ethylacetate-diisopropyl ether (1:5) to give a phenoxyacetamide derivative(3.44 g). The title compound was obtained by similar operations as inReference Example 20, Reference Example 21, Example 10 and Example 6 andusing this compound.

¹H-NMR (DMSO-d₆) δ: 1.26 (3H, d, J=6.6 Hz), 1.65 (4H, m), 2.27 (2H, m),2.43 (2H, m), 3.13 (1H, m), 4.69 (2H, s), 6.93 (2H, d, J=8.7 Hz), 7.23(1H, d, J=8.7 Hz), 7.48 (2H, d, J=8.7 Hz), 7.63-7.69 (4H, m), 7.74 (2H,d, J=8.7 Hz), 10.18 (1H, s).

melting point: 156-158° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 74N-(4′-chloro-1,1′-biphenyl-4-yl)-2-{3-fluoro-4-[1-(1-pyrrolidinyl)ethyl]phenoxy}acetamide

The title compound was obtained by a similar operation as in ReferenceExample 73 and using 1-(2-fluoro-4-hydroxyphenyl)ethanone.

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, d, J=6.6 Hz), 1.65 (4H, m), 2.32 (2H, m),2.43 (2H, m), 3.52 (1H, m), 4.73 (2H, s), 6.79-6.86 (2H, m), 7.38 (1H,m), 7.48 (2H, d, J=8.7 Hz), 7.63-7.69 (4H, m), 7.74 (2H, d, J=9.0 Hz),10.20 (1H, s).

melting point: 154-156° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 75N-(4′-chloro-1,1′-biphenyl-4-yl)-2-{3-methyl-4-[1-(1-pyrrolidinyl)ethyl]phenoxy}acetamide

The title compound was obtained by a similar operation as in ReferenceExample 73 and using 1-(4-hydroxy-2-methylphenyl)ethanone.

¹H-NMR (DMSO-d₆) δ: 1.21 (3H, d, J=6.6 Hz), 1.66 (4H, m), 2.29 (5H, m),2.42 (2H, m), 3.32 (1H, m), 4.66 (2H, s), 6.77-6.80 (2H, m), 7.32 (1H,d, J=8.4 Hz), 7.48 (2H, d, J=8.4 Hz), 7.63-7.69 (4H, m), 7.75 (2H, d,J=8.7 Hz), 10.15 (1H, s).

melting point: 130-132° C. (ethyl acetate-isopropyl ether)

REFERENCE EXAMPLE 76 2-bromo-5-(1-pyrrolidinylmethyl)pyridine

A solution of 2-bromo-5-(bromomethyl)pyridine (9.06 g, 36.1 mmol),pyrrolidine (3.62 ml, 43.3 mmol) and potassium carbonate (9.98 g, 72.2mmol) in acetonitrile (45 ml) was stirred at room temperature for 6 hrs.Ethyl acetate was added to the reaction mixture, and the mixture waswashed with saturated aqueous potassium carbonate solution andsaturated, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the obtained residue was purifiedby NH-silica gel column chromatography (developing solvent; ethylacetate) to give the title compound (7.31 g).

¹H-NMR (CDCl₃) δ: 1.79 (4H, m), 2.49 (4H, m), 3.58 (2H, s), 7.42 (1H, d,J=8.0 Hz), 7.56 (1H, dd, J=8.0, 2.2 Hz), 8.29 (1H, d, J=2.2 Hz).

REFERENCE EXAMPLE 77 1-(3-butynyl)-4-(4-chlorophenyl)piperidine

To a solution (50 ml) of 3-butyn-1-ol (700 mg, 10.0 mmol) andtriethylamine (2.05 ml, 15 mmol) in tetrahydrofuran was addedmethanesulfonyl chloride (1.72 g, 15 mmol) at 0° C., and the mixture wasstirred at room temperature for 1 hr. Ethyl acetate was added to thereaction mixture, and the mixrture was washed with saturated brine anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. 4-(4-Chlorophenyl)piperidine hydrochloride (2.30 g,10.0 mmol), potassium carbonate (1.38 g, 10.0 mmol) and acetonitrile (50ml) were added to the obtained residue, and the mixture was stirred at60° C. for 16 hrs. 2N Hydrochloric acid was added to the reactionmixture, and the mixture was washed with ethyl acetate. The aqueouslayer was basified with 8N aqueous sodium hydroxide solution, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give the title compound (1.31 g) asa solid.

¹H-NMR (CDCl₃) δ: 1.66-1.84 (4H, m), 1.97-2.19 (3H, m), 2.37-2.69 (5H,m), 3.01-3.06 (2H, m), 7.15 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 784-[4-(4-chlorophenyl)-1-piperidinyl]-1-(4-fluorophenyl)-4-oxo-1-butanone

The title compound was obtained by a similar operation as in Example 2and using 4-(4-chlorophenyl)piperidine and4-(4-fluorophenyl)-4-oxobutanoic acid.

¹H-NMR (DMSO-d₆) δ: 1.37-1.42 (1H, m), 1.57-1.65 (1H, m), 1.73-1.84 (2H,m), 2.64 (1H, m), 2.72-2.84 (3H, m), 3.09-3.29 (3H, m), 4.05-4.09 (1H,m), 4.46-4.50 (1H, m), 7.26-7.38 (6H, m), 8.06 (2H, m).

REFERENCE EXAMPLE 79 4-(4-chlorophenyl)-1-(4-phenylbutanoyl)piperidine

The title compound was obtained by a similar operation as in Example 2and using 4-(4-chlorophenyl)piperidine and phenylbutanoic acid.

¹H-NMR (CDCl₃) δ: 1.49-1.59 (2H, m), 1.83-1.87 (2H, m), 1.95-2.02 (2H,m), 2.36 (2H, m), 2.55-2.74 (4H, m), 3.02-3.10 (1H, m), 3.85-3.89 (1H,m), 4.77-4.81 (1H, m), 7.10 (2H, d, J=8.4 Hz), 7.18-7.28 (7H, m).

REFERENCE EXAMPLE 801-(4-{4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxobutyl}phenyl)ethanone

The title compound was obtained by a similar operation as in ReferenceExample 19 and using 4-(4-chlorophenyl)-1-(4-phenylbutanoyl)piperidineobtained in Reference Example 79.

¹H-NMR (DMSO-d₆) δ: 1.34-1.54 (2H, m), 1.73-1.88 (4H, m), 2.36 (2H, t,J=7.5 Hz), 2.55 (4H, m), 2.66-2.80 (3H, m), 3.02-3.10 (1H, m), 3.89-3.93(1H, m), 4.52-4.56 (1H, m), 7.26 (2H, d, J=8.4 Hz), 7.32-7.37 (4H, m),7.88 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 811-(4-{4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxobutyl}phenyl)ethanol

The title compound was obtained by a similar operation as in ReferenceExample 20 and using1-(4-{4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxobutyl}phenyl)ethanoneobtained in Reference Example 80.

¹H-NMR (CDCl₃) δ: 1.49 (3H, d, J=6.3 Hz), 1.59 (2H, m), 1.83-1.88 (2H,m), 1.99 (2H, m), 2.37 (2H, t, J=7.8 Hz), 2.56-2.74 (4H, m), 3.03-3.12(1H, m), 3.87-3.91 (1H, m), 4.77-4.81 (1H, m), 4.87 (1H, m), 7.10 (2H,d, J=8.7 Hz), 7.18 (2H, d, J=8.1 Hz), 7.28 (4H, m).

REFERENCE EXAMPLE 821-{4-[4-(1-chloroethyl)phenyl]butanoyl}-4-(4-chlorophenyl)piperidine

The title compound was obtained by a similar operation as in ReferenceExample 21 and using1-(4-{4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxobutyl}phenyl)ethanolobtained in Reference Example 81.

¹H-NMR (CDCl₃) δ: 1.50-1.63 (2H, m), 1.83-1.88 (5H, m), 1.99 (2H, m),2.37 (2H, t, J=7.5 Hz), 2.56-2.75 (4H, m), 3.03-3.11 (1H, m), 3.86-3.91(1H, m), 4.77-4.81 (1H, m), 5.08 (1H, q, J=6.6 Hz), 7.10 (2H, d, J=8.1Hz), 7.18 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz), 7.33 (2H, d, J=8.1Hz).

REFERENCE EXAMPLE 83N-(4-{4-[4-(4-chlorophenyl)-1-piperidinyl]butanoyl}benzyl)acetamide

The title compound was obtained by a similar operation as in Example 10and using N-[4-(4-chlorobutanoyl)benzyl]acetamide and4-(4-chlorophenyl)piperidine.

¹H-NMR (CDCl₃) δ: 1.56-1.70 (2H, m), 1.75-1.78 (2H, m), 1.92-2.07 (7H,m), 2.43 (3H, m), 2.99 (4H, m), 4.49 (2H, d, J=6.3 Hz), 5.77 (1H, m),7.10 (2H, d, J=8.7 Hz), 7.23 (2H, d, J=8.7 Hz), 7.36 (2H, d, J=8.1 Hz),7.94 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 84 5-bromo-2-(1-pyrrolidinylcarbonyl)pyridine

A solution of 2,5-dibromopyridine (5.00 g, 21.1 mmol),(triphenylphosphine)palladium(II) dichloride (0.44 g, 0.63 mmol),pyrrolidine (1.73 g, 24.27 mmol) and triethylamine (4.33 ml, 31.65 mmol)in toluene (50 ml) was stirred under carbon monoxide (5 atm) atmospherein a stainless bottle at 70° C. for 6 hrs. The reaction solution wasallowed to cool to room temperature, poured into saturated ammoniumchloride solution (200 ml) and extracted with ethyl acetate (200 ml×2).The extract was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromato-silica gel columnchromatography (developing solvent; hexane:ethyl acetate=4:1-1:1) togive a pale-yellow solid.

REFERENCE EXAMPLE 854-(4′-chloro-1,1′-biphenyl-4-yl)-N-methoxy-N-methylbutanamide

The title compound was obtained by a similar operation as in Example 2and using 4-(4′-chloro-1,1′-biphenyl-4-yl)butyric acid andN,O-dimethylhydroxylamine hydrochloride.

¹H-NMR (CDCl₃) δ: 1.98-2.03 (2H, m), 2.47 (2H, t, J=7.2 Hz), 2.72 (2H,t, J=7.5 Hz), 3.18 (3H, s), 3.64 (3H, s), 7.27 (2H, d, J=8.7 Hz), 7.38(2H, d, J=8.7 Hz), 7.45-7.51 (4H, m).

REFERENCE EXAMPLE 86 4-(4-acetylphenyl)-N-methoxy-N-methylbutanamide

The title compound was obtained by a similar operation as in Example 2and using 4-(4-acetylphenyl)butyric acid and N,O-dimethylhydroxylaminehydrochloride.

¹H-NMR (CDCl₃) δ: 1.99 (2H, m), 2.45 (2H, t, J=7.5 Hz), 2.59 (3H, s),2.74 (2H, t, J=7.5 Hz), 3.18 (3H, s), 3.64 (3H, s) 7.30 (2H, d, J=8.2Hz), 7.89 (2H, d, J=8.2 Hz).

REFERENCE EXAMPLE 874-[4-(1-hydroxyethyl)phenyl]-N-methoxy-N-methylbutanamide

The title compound was obtained by a similar operation as in ReferenceExample 20 and using 4-(4-acetylphenyl)-N-methoxy-N-methylbutanamideobtained in Reference Example 86.

¹H-NMR (CDCl₃) δ: 1.49 (3H, d, J=6.3 Hz), 1.80 (1H, d, J=3.6 Hz), 1.96(2H, m), 2.44 (2H, t, J=7.2 Hz), 2.67 (2H, t, J=7.2 Hz), 3.17 (3H, s),3.63 (3H, s), 4.86-4.90 (1H, m), 7.19 (2H, d, J=7.8 Hz), 7.29 (2H, d,J=7.8 Hz).

REFERENCE EXAMPLE 884-[4-(1-chloroethyl)phenyl]-N-methoxy-N-methylbutanamide

The title compound was obtained by a similar operation as in ReferenceExample 21 and using4-[4-(1-hydroxyethyl)phenyl]-N-methoxy-N-methylbutanamide obtained inReference Example 87.

¹H-NMR (CDCl₃) δ: 1.84 (3H, d, J=6.9 Hz), 1.97 (2H, m), 2.44 (2H, t,J=7.2 Hz), 3.17 (3H, s), 3.63 (3H, s), 5.09 (1H, q, J=8.1 Hz), 7.34 (2H,d, J=8.1 Hz).

REFERENCE EXAMPLE 89N-methoxy-N-methyl-4-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}butanamide

The title compound was obtained by a similar operation as in Example 10and using 4-[4-(1-chloroethyl)phenyl]-N-methoxy-N-methylbutanamideobtained in Reference Example 88 and pyrrolidine.

¹H-NMR (CDCl₃) δ: 1.38 (3H, d, J=6.6 Hz), 1.73-1.77 (4H, m), 1.96 (2H,m), 2.33-2.38 (2H, m), 2.43 (2H, t, J=7.2 Hz), 2.51-2.55 (2H, m), 2.66(2H, t, J=7.2 Hz), 3.15 (1H, q, J=6.6 Hz), 3.17 (3H, s), 3.62 (3H, s),7.13 (2H, d, J=7.8 Hz), 7.25 (2H, d, J=7.8 Hz).

REFERENCE EXAMPLE 904-(4-chlorophenyl)-1-{4-[5-(1-pyrrolidinylmethyl)-2-pyridyl]-3-butynyl}piperidine

2-Bromo-5-(1-pyrrolidinylmethyl)pyridine (243 mg, 1.01 mmol) obtained inReference Example 76, 1-(3-butynyl)-4-(4-chlorophenyl)piperidine (500mg, 2.02 mmol) obtained in Reference Example 77 andtetrakistriphenylphosphine palladium (58.3 mg, 50.5 μmol) in pyrrolidine(5 ml) were stirred at 80° C. for 2 hrs. The reaction mixture wasconcentrated under reduced pressure, and ethyl acetate was added to theresidue. The mixture was washed with saturated aqueous potassiumhydrogencarbonate solution and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure, andthe obtained residue was purified by NH-silica gel column chromatography(developing solvent; ethyl acetate), and powderized with hexane to givethe title compound (278 mg).

¹H-NMR (CDCl₃) δ: 1.79 (8H, m), 2.11-2.24 (2H, m), 2.50 (5H, m),2.64-2.76 (4H, m), 3.05-3.11 (2H, m), 3.60 (2H, s), 7.15 (2H, d, J=8.6Hz), 7.26 (2H, d, J=8.6 Hz), 7.33 (1H, d, J=8.2 Hz), 7.62 (1H, dd,J=8.2, 2.2 Hz), 8.47 (1H, d, J=2.2 Hz).

melting point: 86-88° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 408 [M+H]+

REFERENCE EXAMPLE 914-[4-(4-chlorophenyl)-1-piperidinyl]-1-[5-(1-pyrrolidinylmethyl)-2-pyridyl]-2-butanonetrihydrochloride

To a solution of4-(4-chlorophenyl)-1-{4-[5-(1-pyrrolidinylmethyl)-2-pyridyl]-3-butynyl}piperidine(200 mg, 0.490 mmol) obtained in Reference Example 90 in methanol (1 ml)was added a solution (5 ml) of HgO (35.3 mg, 0.163 mmol) in 40% aqueoussulfuric acid, and the mixture was stirred at 60° C. for 6 hrs. Ethylacetate was added to the reaction mixture, and the mixture was washedwith saturated aqueous potassium hydrogencarbonate solution andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue waspurified by alumina column chromatography (developing solvent; ethylacetate). 4N Hydrogen chloride-ethyl acetate was added to the obtainedoil, and the mixture was powderized with isopropyl ether to give thetitle compound (84.4 mg).

¹H-NMR (free base, CDCl₃) δ: 1.78 (8H, m), 1.98-2.10 (2H, m), 2.50 (5H,m), 2.66-2.79 (4H, m), 2.94-2.99 (2H, m), 3.61 (2H, s), 3.93 (2H, s),7.10-7.26 (5H, m), 7.26 (2H, d, J=8.6 Hz), 7.68 (1H, m), 8.48 (1H, m).

FABMS (pos) 426 [M+H]+

REFERENCE EXAMPLE 924-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxo-1-[4-(1-pyrrolidinylmethyl)phenyl]-1-butanone

The title compound was obtained by similar operations as in ReferenceExample 32, Reference Example 28 and Example 2 and using methyl4-[4-(bromomethyl)phenyl]-4-oxobutanoate.

¹H-NMR (DMSO-d₆) δ: 1.37-1.79 (8H, m), 2.43 (4H, m), 2.61-2.80 (4H, m),3.07-3.23 (3H, m), 3.64 (2H, s), 4.08 (1H, m), 4.50 (1H, m), 7.32 (4H,m), 7.46 (2H, d, J=8.4 Hz), 7.94 (2H, d, J=8.4 Hz).

melting point: 105-106° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 439 [M+H]+

REFERENCE EXAMPLE 934-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxo-1-[4-(1-pyrrolidinylmethyl)phenyl]-1-butanol

The title compound was obtained by a similar operation as in ReferenceExample 20 and using4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxo-1-[4-(1-pyrrolidinylmethyl)phenyl]-1-butanoneobtained in Reference Example 92.

¹H-NMR (DMSO-d₆) δ: 1.43 (2H, m), 1.67-1.86 (8H, m), 2.40 (6H, m),2.55-2.82 (2H, m), 3.05 (1H, m), 3.54 (2H, s), 3.87 (1H, m), 4.57 (2H,m), 5.19 (1H, m), 7.25-7.37 (8H, m).

melting point: 110-112° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 441 [M+H]+

REFERENCE EXAMPLE 944-(4-chlorophenyl)-1-{(E)-4-[4-(1-pyrrolidinylmethyl)phenyl]-3-butenoyl}piperidine

Using methyl 4-[4-(bromomethyl)phenyl]-4-oxobutanoate, a similaroperation as in Reference Example 32 was performed. To a solution of theobtained oil (1.27 g, 4.61 mmol) in methanol (11 ml) was added sodiumborohydride (174 mg, 4.61 mmol), and the mixture was stirred for 2 hrs.Ethyl acetate was added to the reaction mixture, and the mixture waswashed with saturated aqueous potassium hydrogencarbonate solution andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to give an alcohol compound (1.17g). Concentrated hydrochloric acid (20 ml) was added to the obtainedalcohol compound, and the mixture was stirred at 100° C. for 16 hrs. Thereaction mixture was concentrated, and toluene was added to the residue,and the mixture was concentrated. The title compound was obtained by asimilar operation as in Example 2 and using the obtained carboxylicacid.

¹H-NMR (CDCl₃) δ: 1.59 (2H, m), 1.78 (4H, m), 1.88 (2H, m), 2.49 (4H,m), 2.61-2.76(2H, m), 3.16 (1H, m), 3.34 (2H, d, J=6.6 Hz), 3.59 (2H,s), 4.02 (1H, m), 4.80 (1H, m), 6.33 (1H, dt, J=6.6, 16.2 Hz), 6.48 (1H,d, J=16.2 Hz), 7.10 (2H, d, J=8.7 Hz), 7.28 (6H, m)

melting point: 105-106° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 423 [M+H]+

REFERENCE EXAMPLE 954-[4-(4-chlorophenyl)-1-piperidinyl]-1-[4-(4-methyl-1-piperazinyl)phenyl]-4-oxo-1-butanone

A solution (6 ml) of4-[4-(4-chlorophenyl)-1-piperidinyl]-1-(4-fluorophenyl)-4-oxo-1-butanone(1.00 g, 2.67 mmol) obtained in Reference Example 78 andN-methylpiperazine (0.89 ml, 8.02 mmol) in dimethylsulfoxide was stirredat 100° C. for 16 hrs. Ethyl acetate was added to the reaction mixture,and the mixture was washed with aqueous saturated sodium carbonatesolution and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure, and the obtainedresidue was purified by alumina column chromatography (developingsolvent; ethyl acetate), and powderized with isopropyl ether to give thetitle compound (1.06 g).

¹H-NMR (DMSO-d₆) δ: 1.42-1.78 (4H, m), 2.23 (3H, s), 2.44-2.51 (7H, m),2.65-2.80 (3H, m), 3.13 (5H, m), 4.07 (1H, m), 4.47 (1H, m), 6.98 (2H,d, J=9.2 Hz), 7.31 (4H, m), 7.85 (2H, d, J=9.2 Hz).

melting point: 152-153° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 454 [M+H]+

REFERENCE EXAMPLE 961-(4-{4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxobutyl}phenyl)-4-methylpiperazine

A solution (2 ml) of4-[4-(4-chlorophenyl)-1-piperidinyl]-1-[4-(4-methyl-1-piperazinyl)phenyl]-4-oxo-1-butanone(500 mg, 1.10 mmol) obtained in Reference Example 95 and triethylsilane(0.53 ml) in trifluoroacetic acid was stirred at room temperature for 16hrs. Ethyl acetate was added to the reaction mixture. The mixture waswashed with 8N aqueous sodium hydroxide solution and saturated brine,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The obtained residue was purified by NH-silicacolumn chromatography (developing solvent; ethyl acetate:hexane=1:2),and powderized with isopropyl ether to give the title compound (129 mg).

¹H-NMR (DMSO-d₆) δ: 1.43 (2H, m), 1.75 (4H, m), 2.21 (3H, s), 2.31 (2H,m), 2.41-2.54 (7H, m), 2.76 (1H, m), 3.06 (5H, m), 3.90 (1H, m), 4.54(1H, m), 6.83 (2H, d, J=8.8 Hz), 7.03 (2H, d, J=8.8 Hz), 7.30 (4H, m).

melting point: 119-120° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 440 [M+H]+

REFERENCE EXAMPLE 974-(4-chlorophenyl)-1-(4-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}butanoyl)piperidinehydrochloride

The title compound was obtained by a similar operation as in Example 10and using1-{4-[4-(1-chloroethyl)phenyl]butanoyl}-4-(4-chlorophenyl)piperidineobtained in Reference Example 82.

¹H-NMR (CDCl₃, free base) δ: 1.38 (3H, d, J=6.6 Hz), 1.49-1.63 (2H, m),1.74 (4H, m), 1.82-1.86 (2H, m), 1.98 (2H, m), 2.35 (4H, m), 2.50-2.74(6H, m), 3.02-3.10 (1H, m), 3.14 (1H, q, J=6.6 Hz), 3.84-3.89 (1H, m),4.77-4.81 (1H, m), 7.10 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.1 Hz),7.22-7.28 (4H, m).

FABMS (pos) 439 [M+H]+

REFERENCE EXAMPLE 981-[4-(aminomethyl)phenyl]-4-[4-(4-chlorophenyl)-1-piperidinyl]-1-butanone

A solution ofN-(4-{4-[4-(4-chlorophenyl)-1-piperidinyl]butanoyl}benzyl)acetamide (150mg, 0.363 mmol) obtained in Reference Example 83 in concentratedhydrochloric acid (2 ml) was stirred at 100° C. for 16 hrs. The reactionmixture was basified with potassium carbonate and extracted with ethylacetate. The extract was washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and powderized with hexane to give the title compound (104mg).

¹H-NMR (CDCl₃) δ: 1.55-1.79 (6H, m), 1.95-2.08 (4H, m), 2.45 (3H, m),3.00 (4H, m), 3.94 (2H, s), 7.11 (2H, d, J=8.7 Hz), 7.23 (2H, d, J=8.7Hz), 7.41 (2H, d, J=8.1 Hz), 7.95 (2H, d, J=8.1 Hz).

melting point: 94-96° C. (ethyl acetate-hexane)

REFERENCE EXAMPLE 994-[4-(4-chlorophenyl)-1-piperidinyl]-1-[4-(1-pyrrolidinylmethyl)phenyl]-1-butanone

A solution of1-[4-(aminomethyl)phenyl]-4-[4-(4-chlorophenyl)-1-piperidinyl]-1-butanone(50.0 mg, 0.135 mmol) obtained in Reference Example 98,1,4-dibromobutane (16.1 μl, 0.135 mmol) and sodium carbonate (42.9 mg,0.404 mmol) in dimethylformamide (1 ml) was stirred at 80° C. for 16hrs. Ethyl acetate was added to the reaction mixture, and the mixturewas washed with saturated aqueous potassium carbonate solution andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue waspurified by alumina column chromatography (developing solvent; ethylacetate:hexane=1:3) to give the title compound (13.7 mg).

¹H-NMR (CDCl₃) δ: 1.60-1.81 (8H, m), 1.95-2.06 (4H, m), 2.41-2.50 (7H,m), 2.97-3.03 (4H, m), 3.66 (2H, s), 7.10 (2H, d, J=8.4 Hz), 7.24 (2H,d, J=8.4 Hz), 7.42 (2H, d, J=8.1 Hz), 7.93 (2H, d, J=8.1 Hz).

melting point: 63-65° C. (ethyl acetate-hexane)

FABMS (pos) 425 [M+H]+

REFERENCE EXAMPLE 1004-(4-chlorophenyl)-1-{4-[2-fluoro-4-(1-pyrrolidinylmethyl)phenyl]-3-butynyl}piperidine

The title compound was obtained by similar operations as in Example 10and Reference Example 90 and using1-bromo-4-bromomethyl-2-fluorobenzene, pyrrolidine and1-(3-butynyl)-4-(4-chlorophenyl)piperidine obtained in Reference Example77.

¹H-NMR (CDCl₃) δ: 1.77-1.86 (8H, m), 2.09-2.25 (2H, m), 2.41-2.75 (9H,m), 3.04-3.06 (2H, m), 3.56 (2H, s), 7.01-7.32 (7H, m).

REFERENCE EXAMPLE 1014-(4-chlorophenyl)-1-{4-[3-fluoro-4-(1-pyrrolidinylmethyl)phenyl]-3-butynyl}piperidine

The title compound was obtained by similar operations as in Example 10and Reference Example 90 and using1-bromo-4-bromomethyl-3-fluorobenzene, pyrrolidine and1-(3-butynyl)-4-(4-chlorophenyl) obtained in piperidine ReferenceExample 77.

¹H-NMR (CDCl₃) δ: 1.69-1.84(8H, m), 2.12-2.25 (2H, dt like), 2.43-2.75(9H, m), 3.05-3.11 (2H, d like), 3.65 (2H, s), 7.03-7.17 (4H, m),7.24-7.34 (3H, m).

FABMS (pos) 425 [M+H]+

REFERENCE EXAMPLE 1024-(4-chlorophenyl)-1-{4-[2-methyl-4-(1-pyrrolidinylmethyl)phenyl]-3-butynyl}piperidine

The title compound was obtained by a similar operation as in ReferenceExample 90 and using 1-(4-bromo-3-methylbenzyl)pyrrolidine and1-(3-butynyl)-4-(4-chlorophenyl)piperidine obtained in Reference Example77.

¹H-NMR (CDCl₃) δ: 1.73-1.92 (8H, m), 2.14-2.23 (2H, m), 2.34 and 2.40(3H, s), 2.44-2.52 (5H, m), 2.60-2.75 (4H, m), 3.07-3.11 (2H, m), 3.55and 3.57 (2H, s), 7.12-7.28 (7H, m).

REFERENCE EXAMPLE 1034-(4-chlorophenyl)-1-{4-[3-methyl-4-(1-pyrrolidinylmethyl)phenyl]-3-butynyl}piperidine

The title compound was obtained by a similar operation as in ReferenceExample 90 and using 1-(4-bromo-2-methylbenzyl)pyrrolidine and1-(3-butynyl)-4-(4-chlorophenyl)piperidine obtained in Reference Example77.

¹H-NMR (CDCl₃) δ: 1.75-1.81 (8H, m), 2.14-2.22 (2H, m) 2.31 and 2.35(3H, s), 2.44-2.54 (5H, m), 2.59-2.64 (2H, m), 2.69-2.75 (2H, m),3.06-3.10 (2H, m), 3.55 and 3.58 (2H, s), 7.12-7.29 (7H, m).

REFERENCE EXAMPLE 1044-(4-chlorophenyl)-1-{4-[6-(1-pyrrolidinylmethyl)-3-pyridyl]-3-butynyl}piperidine

To a solution of 5-bromo-2-(1-pyrrolidinylcarbonyl)pyridine (500 mg,2.00 mmol) obtained in Reference Example 84 in ether (20 ml) was addedlithium aluminum hydride (150 mg, 4.00 mmol), and the mixture wasstirred for 15 min. To a reaction solution were successively added ethylacetate (5 ml) and water (5 ml), and the mixture was filtered throughcelite. The filtrate was partitioned between ethyl acetate (20 ml) andwater (20 ml). The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The title compound was obtained by a similar operationas in Reference Example 90 and using the obtained5-bromo-2-(1-pyrrolidinylmethyl)pyridine and1-(3-butynyl)-4-(4-chlorophenyl)piperidine obtained in Reference Example77.

¹H-NMR (CDCl₃) δ: 1.71-1.83 (8H, m), 2.13-2.25 (2H, m), 2.44-2.77 (9H,m), 3.05-3.11 (2H, br m), 3.76 (2H, s), 7.15 (2H, d, J=8.4 Hz),7.27-7.35 (3H, m), 7.64 (1H, dd, J=2.2 Hz, 8.2 Hz), 8.57 (1H, d, J=2.2Hz).

FABMS (pos) 408 [M+H]+

REFERENCE EXAMPLE 1054-[4-(4-chlorophenyl)-1-piperidinyl]-1-[2-fluoro-4-(1-pyrrolidinylmethyl)phenyl]-1-butanonedihydrochloride

The title compound was obtained by a similar operation as in ReferenceExample 91 and using4-(4-chlorophenyl)-1-{4-[2-fluoro-4-(1-pyrrolidinylmethyl)phenyl]-3-butynyl}piperidineobtained in Reference Example 100.

¹H-NMR (free base, CDCl₃) δ: 1.66-2.11 (1OH, m), 2.40-2.51 (9H, m),2.95-3.06 (4H, m), 3.64 (2H, s), 7.08-7.28 (6H, m), 7.83 (1H, t, J=8.0Hz).

FABMS (pos) 443 [M+H]+

REFERENCE EXAMPLE 1064-[4-(4-chlorophenyl)-1-piperidinyl]-1-[3-fluoro-4-(1-pyrrolidinylmethyl)phenyl]-1-butanone

The title compound was obtained by a similar operation as in ReferenceExample 91 and using4-(4-chlorophenyl)-1-{4-[3-fluoro-4-(1-pyrrolidinylmethyl)phenyl]-3-butynyl}piperidineobtained in Reference Example 101.

¹H-NMR (CDCl₃) δ: 1.54-1.82 (8H, m), 1.94-2.08 (2H, m), 2.39-2.60 (9H,m), 2.93-3.00 (4H, m), 3.73 (2H, s), 7.08-7.26 (5H, m), 7.48-7.76 (2H,m).

FABMS (pos) 443 [M+H]+

REFERENCE EXAMPLE 1074-[4-(4-chlorophenyl)-1-piperidinyl]-1-[2-methyl-4-(1-pyrrolidinylmethyl)phenyl]-1-butanone

The title compound was obtained by a similar operation as in ReferenceExample 91 and using4-(4-chlorophenyl)-1-{4-[2-methyl-4-(1-pyrrolidinylmethyl)phenyl]-3-butynyl}piperidineobtained in Reference Example 102.

¹H-NMR (CDCl₃) δ: 1.70-1.81 (8H, m), 1.90-2.04 (4H, m), 2.34 and 2.38(3H, s), 2.34-2.50 (9H, m), 2.90-3.05 (2H, m), 3.57 and 3.61 (2H, s),7.03-7.27 (6H, m), 7.63-7.67 (1H, m).

FABMS (pos) 439 [M+H]+

REFERENCE EXAMPLE 1084-[4-(4-chlorophenyl)-1-piperidinyl]-1-[3-methyl-4-(1-pyrrolidinylmethyl)phenyl]-1-butanone

The title compound was obtained by a similar operation as in ReferenceExample 91 and using4-(4-chlorophenyl)-1-{4-[3-methyl-4-(1-pyrrolidinylmethyl)phenyl]-3-butynyl}piperidineobtained in Reference Example 103.

¹H-NMR (CDCl₃) δ: 1.64-1.80 (8H, m), 1.93-2.09 (4H, m) 2.36 and 2.41(3H, s), 2.36-2.55 (9H, m), 2.94-3.04 (2H, m), 3.59 and 3.62 (2H, s),7.08-7.31 (6H, m), 7.75-7.78 (1H, m).

FABMS (pos) 439 [M+H]+

REFERENCE EXAMPLE 1094-[4-(4-chlorophenyl)-1-piperidinyl]-1-[6-(1-pyrrolidinylmethyl)-3-pyridyl]-1-butanone

The title compound was obtained by a similar operation as in ReferenceExample 91 and using4-(4-chlorophenyl)-1-{4-[6-(1-pyrrolidinylmethyl)-3-pyridyl]-3-butynyl}piperidineobtained in Reference Example 104.

¹H-NMR (CDCl₃) δ: 1.53-1.81 (8H, m), 1.97-2.08 (2H, m) 2.41-2.70 (9H,m), 2.97-3.03 (4H, m), 3.84 (2H, s), 7.09 (2H, d, J=8.4 Hz), 7.24 (2H, doverlapping with CDCl₃), 7.54 (1H, d, J=8.4 Hz), 8.23 (1H, dd, J=1.9 Hz,8.4 Hz), 9.13 (1H, d, J=1.9 Hz)

FABMS (pos) 426 [M+H]+

REFERENCE EXAMPLE 1104-(4′-chloro-1,1′-biphenyl-4-yl)-1-[4-(1-pyrrolidinylmethyl)phenyl]-1-butanone

To a solution of 1-(4-bromobenzyl)pyrrolidine (240 mg, 1.00 mmol) in THF(7 ml) was added dropwise a solution (1.6 M, 0.63 ml) of n-butyllithiumin hexane under a nitrogen atmosphere at −78° C. The obtained solutionwas stirred at −78° C. for 30 min., allowed to warm to −40° C., and asolution of4-(4′-chloro-1,1′-biphenyl-4-yl)-N-methoxy-N-methylbutanamide (320 mg,1.00 mol) obtained in Reference Example 85 in THF (3 ml) was addeddropwise. The obtained solution was stirred at −40° C. for 30 min., andthen at room temperature for 16 hrs. The reaction solution was pouredinto saturated ammonium chloride solution (40 ml) and extracted withethyl acetate (40 ml×2). The extract was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by alumina columnchromatography (developing solvent; hexane:ethyl acetate=20:1), and theobtained colorless solid was disrupted in isopropyl ether to give thetitle compound.

¹H-NMR (CDCl₃) δ: 1.76-1.82 (4H, m), 2.04-2.18 (2H, m), 2.47-2.54 (4H,m), 2.76 (2H, t, J=7.4 Hz), 3.00 (2H, ti J=7.4 Hz), 3.65 (2H, s), 7.28(2H, d, J=8.2 Hz), 7.36-7.53 (8H, m), 7.88 (2H, d, J=8.6 Hz).

melting point: 114-115° C. (isopropyl ether)

FABMS (pos) 418 [M+H]+

REFERENCE EXAMPLE 1111-phenyl-4-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}-1-butanone hydrochloride

To a solution of phenylmagnesium bromide (2 mol/l THF solution, 1.6 ml)in toluene (7 ml) was added dropwise a solution ofN-methoxy-N-methyl-4-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}butanamide (200mg, 0.66 mmol) obtained in Reference Example 89 in toluene (3 ml) undera nitrogen atmosphere under ice-cooling. After stirring at roomtemperature for 1 hr, the reaction solution was poured into water (40ml), and extracted with ethyl acetate (40 ml×2). The extract was washedsuccessively with 10% sodium hydrogencarbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified byNH-silica gel column chromatography (developing solvent; hexane:ethylacetate=10:1) to give a colorless oil. The oil was dissolved in ethylacetate (10 ml), and 4N-hydrochloric acid (ethyl acetate solution; 0.2ml) was added dropwise under ice-cooling. The mixture was stirred for 5min., and the solvent was evaporated under reduced pressure. The residuewas powderized with isopropyl ether and hexane, and washed with hexaneto give the title compound.

¹H-NMR (free base, CDCl₃) δ: 1.39 (3H, d, J=6.6 Hz), 1.73-1.77 (4H, m),2.03-2.12 (2H, m), 2.34-2.37 (2H, m), 2.53-2.59 (2H, m), 2.70 (2H, t,J=7.5 Hz), 2.98 (2H, t, J=7.5 Hz), 3.15 (1H, q, J=6.6 Hz), 7.14 (2H, d,J=8.1 Hz), 7.23-7.35 (3H, m), 7.40-7.44 (2H, m), 7.92 (2H, d like).

melting point: 116-117° C. (hexane)

FABMS (pos) 322 [M+H]+

REFERENCE EXAMPLE 1121-[1,1′-biphenyl-4-yl]-4-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}-1-butanone

The title compound was obtained by a similar operation as in ReferenceExample 111 and usingN-methoxy-N-methyl-4-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}butanamideobtained in Reference Example 89 and 4-biphenylmagnesium bromide.

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=6.6 Hz), 1.71-1.80 (4H, m), 2.10 (2H,m), 2.34-2.39 (2H, m), 2.51-2.56 (2H, m), 2.72 (2H, t, J=7.5 Hz), 3.01(2H, t, J=7.5 Hz), 3.16 (1H, q, J=6.6 Hz), 7.15 (2H, d, J=7.8 Hz),7.24-7.27 (2H, m), 7.37-7.50 (3H, m), 7.60-7.68 (4H, m), 7.99 (2H, m).

melting point: 70-72° C. (hexane)

FABMS (pos) 398 [M+H]+

REFERENCE EXAMPLE 1131-(4′-chloro-1,1′-biphenyl-4-yl)-4-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}-1-butanone

The title compound was obtained by a similar operation as in ReferenceExample 110 and usingN-methoxy-N-methyl-4-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}butanamideobtained in Reference Example 89 and 4-bromo-4′-chlorobiphenyl.

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=6.6 Hz), 1.73-1.75 (4H, m), 2.09 (2H,m), 2.34-2.41 (2H, m), 2.51-2.61 (2H, m), 2.71 (2H, t; J=7.7 Hz), 3.00(2H, t, J=7.7 Hz), 3.16 (1H, q, J=6.6 Hz), 7.15 (2H, d, J=7.9 Hz), 7.26(2H, d, J=7.9 Hz), 7.43 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.62(2H, d, J=8.2 Hz), 7.99 (2H, d, J=8.2 Hz).

melting point: 81-82° C. (hexane)

FABMS (pos) 432 [M+H]+

REFERENCE EXAMPLE 1141-[1-(4-{3-[(4′-chloro-1,1′-biphenyl-4-yl)sulfonyl]propyl}phenyl)ethyl]pyrrolidine

To a solution of 1-bromo-4-[(3-phenylpropyl)thio]benzene (5.00 g, 16.3mmol) in chloroform (80 ml) was added mCPBA (10.2 g, 40.7 mmol), and themixture was stirred at room temperature for 2 hrs. The solvent wasevaporated, and the residue was dissolved in ethyl acetate, and thesolution was washed with aqueous potassium carbonate solution andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the obtained residue waspurified by alumina column chromatography (developing solvent; ethylacetate:hexane=3:1), and powderized with hexane to give a sulfonederivative (4.81 g). The title compound was obtained by similaroperations as in Reference Example 19-21, Example 10 and Example 6 andusing this compound.

¹H-NMR (CDCl₃) δ: 1.37 (3H, d, J=6.6 Hz), 1.76 (4H, m), 2.07 (2H, m),2.32 (2H, m), 2.51 (2H, m), 2.69 (2H, m), 3.13 (3H, m), 7.04 (2H, d,J=8.1 Hz), 7.23 (2H, d, J=8.1 Hz), 7.46 (2H, d, J=8.7 Hz), 7.55 (2H, d,J=8.7 Hz), 7.72 (2H, d, J=8.7 Hz), 7.92 (2H, d, J=8.7 Hz).

EXAMPLE 14-(4-chlorophenyl)-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}-1-piperidinecarboxamide

To a solution of 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine (229 mg,1.12 mmol) obtained in Reference Example 4 in dimethylacetamide (5.6 ml)was added carbonyldiimidazole (218 mg, 1.34 mmol) at 0° C., and themixture was stirred for 1 hr. 4-(4-Chlorophenyl)piperidine hydrochloride(286 mg, 1.23 mmol) was added, and the mixture was stirred at roomtemperature for 5 hrs. Ethyl acetate was added to the reaction mixture,and the mixture was washed with saturated aqueous potassium carbonatesolution and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure, and the obtainedresidue was purified by alumina column chromatography (developingsolvent; ethyl acetate:hexane=3:1), and powderized with hexane to givethe title compound (151 mg).

¹H-NMR (DMSO-d₆) δ: 1.57 (2H, m), 1.77 (5H, m), 2.49 (4H, m), 2.63 (1H,m), 2.83 (4H, m), 3.50 (2H, m), 3.58 (2H, m), 3.99 (2H, m), 4.48 (1H,m), 7.13 (4H, m), 7.27 (4H, m).

melting point: 116-117° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 426 [M+H]⁺

EXAMPLE 24′-chloro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

To a solution of 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine (108 mg,0.529 mmol) obtained in Reference Example 4,4′-chloro[1,1′-biphenyl]-4-carboxylic acid (148 mg, 0.624 mmol) and1-hydroxybenzotriazole (71.4 mg, 0.624 mmol) in dimethylformamide (1.5ml) was added ethyldimethylaminopropylcarbodiimide hydrochloride (122mg, 0.624 mmol) at 0° C., and the mixture was stirred at roomtemperature for 16 hrs. Ethyl acetate was added to the reaction mixture,and the mixture was washed with aqueous potassium carbonate solution andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas concentrated under reduced pressure, and the obtained residue waspurified by NH-silica column chromatography (developing solvent; ethylacetate), and powderized with isopropyl ether to give the title compound(112 mg).

¹H-NMR (DMSO-d₆) δ: 1.67 (4H, m), 2.39 (4H, m), 2.83 (2H, t, J=7.5 Hz),3.47 (2H, m), 3.51 (2H, s), 7.20 (4H, m), 7.53 (2H, d, J=8.7 Hz), 7.76(4H, m), 7.91 (2H, d, J=8.7 Hz), 8.62 (1H, t, J=5.7 Hz).

melting point: 165-167° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 419 [M+H]⁺

EXAMPLE 3 4-pentyl-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (DMSO-d₆) δ: 0.86 (3H, t, J=6.9 Hz), 1.27 (4H, m), 1.57 (2H, m),1.67 (4H, m), 2.41 (4H, m), 2.60 (2H, t, J=7.8 Hz), 2.81 (2H, t, J=7.8Hz), 3.44 (2H, m), 3.52 (2H, s), 7.18 (4H, m), 7.25 (2H, d, J=8.4 Hz),7.71 (2H, d, J=8.4 Hz), 8.44 (1H, m).

melting point: 91-93° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 379 [M+H]⁺

EXAMPLE 44-(2-oxopentyl)-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (DMSO-d₆) δ: 0.82 (3H, t, J=7.4 Hz), 1.48 (2H, m), 1.67 (4H, m),2.39 (4H, m), 2.44 (2H, m), 2.81 (2H, m), 3.48 (2H, m), 3.51 (2H, s),3.81 (2H, s), 7.19 (4H, m), 7.24 (2H, d, J=8.2 Hz), 7.74 (2H, d, J=8.2Hz), 8.50 (1H, m).

melting point: 115-117° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 393 [M+H)⁺

EXAMPLE 54-bromo-2-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]propyl}benzamide

The title compound was obtained by similar operations as in ReferenceExample 4 and Example 2 and using tert-butyl2-[4-(1-pyrrolidinylmethyl)phenyl]propylcarbamate obtained in ReferenceExample 13.

¹H-NMR (CDCl₃) δ: 1.33 (3H, d, J=7.2 Hz), 1.78 (4H, m), 2.51 (4H, m),3.03 (1H, m), 3.46 (1H, m), 3.59 (2H, s), 3.79 (1H, m), 6.50 (1H, m),7.16-7.30 (5H, m), 7.37 (1H, m), 7.92 (1H, m).

melting point: 80-82° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 419 [M+H]⁺

EXAMPLE 64′-chloro-3-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]propyl}1,1′-biphenyl]-4-carboxamide

To a solution (7 ml) of4-bromo-2-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]propyl}benzamide(300 mg, 0.715 mmol) obtained in Example 5, 4-chlorophenylboronic acid(224 mg, 1.43 mmol) and 2N aqueous sodium carbonate solution (715 ml) intetrahydrofuran was added tetrakistriphenylphosphine palladium (24.8 mg,21.5 mmol) under a nitrogen atmosphere. This was stirred at 90° C. for16 hrs, and allowed to cool to room temperature. Ethyl acetate was addedto the reaction mixture, and the mixture was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, and the obtained residue was purified byNH-silica gel column chromatography (developing solvent; ethyl acetate),and powderized with isopropyl ether to give the title compound (142 mg).

¹H-NMR (DMSO-d₆) δ: 1.24 (3H, d, J=7.0 Hz), 1.67 (4H, m), 2.41 (4H, m),3.03 (1H, m), 3.40 (2H, m), 3.53 (2H, s), 7.22 (4H, m), 7.52-7.65 (5H,m), 7.77 (2H, d, J=8.6 Hz), 8.33 (1H, m).

melting point: 119-121° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 451 [M+H]⁺

EXAMPLE 74′-chloro-3-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamineobtained in Reference Example 4.

¹H-NMR (DMSO-d₆) δ: 1.68 (4H, m), 2.42 (4H, m), 2.83 (2H, m), 3.48 (2H,m), 3.54 (2H, s), 7.21 (4H, m), 7.53-7.70 (5H, m), 7.79 (2H, d, J=8.4Hz), 8.39 (1H, m).

melting point: 128-131° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 437 [M+H]⁺

EXAMPLE 84′-chloro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]propyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in ReferenceExample 4 and Example 2 and using tert-butyl2-[4-(1-pyrrolidinylmethyl)phenyl]propylcarbamate obtained in ReferenceExample 13.

¹H-NMR (DMSO-d₆) δ: 1.23 (3H, d, J=6.9 Hz), 1.68 (4H, m), 2.43 (4H, m),3.09 (1H, m), 3.33-3.44 (2H, m), 3.56 (2H, s), 7.22 (4H, m), 7.55 (2H,d, J=8.4 Hz), 7.75 (4H, m), 7.88 (2H, d, J=8.4 Hz), 8.55 (1H, m).

melting point: 156-157° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 433 [M+H]⁺

EXAMPLE 9 4-pentyl-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]propyl}benzamide

The title compound was obtained by similar operations as in ReferenceExample 4 and Example 2 and using tert-butyl2-[4-(1-pyrrolidinylmethyl)phenyl]propylcarbamate obtained in ReferenceExample 13.

¹H-NMR (DMSO-d₆) δ: 1.85 (3H, t, J=6.8 Hz), 1.22 (3H, d, J=6.6 Hz), 1.28(4H, m), 1.57 (2H, m), 1.67 (4H, m), 2.39 (4H, m), 2.59 (2H, t, J=7.4Hz), 3.04 (1H, m), 3.37 (2H, m), 3.51 (2H, s), 7.20 (6H, m), 7.68 (2H,d, J=8.4 Hz), 8.38 (1H, m).

melting point: 91-92° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 393 [M+H]⁺

EXAMPLE 104-bromo-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

A solution of 4-bromo-N-{2-[4-(1-chloroethyl)phenyl]ethyl}benzamide(1.49 g, 4.06 mmol) obtained in Reference Example 14, pyrrolidine (1.02ml, 12.2 mmol) and potassium carbonate (1.68 g, 12.2 mmol) indimethylformamide (10 ml) was stirred at 80° C. for 16 hrs. Diethylether was added to the reaction mixture, and the mixture was washed withsaturated brine and extracted with 1N hydrochloric acid. The extract waswashed with diethyl ether, basified with potassium carbonate andextracted with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure, and the obtained residue waspurified by alumina column chromatography (developing solvent; ethylacetate), and powderized with isopropyl ether-hexane (1:1) to give thetitle compound (1.00 g).

¹H-NMR (DMSO-d₆) δ: 1.26 (3H, d, J=6.6 Hz), 1.64 (4H, m), 2.25 (2H, m),2.42 (2H, m), 2.81 (2H, m), 3.14 (1H, m), 3.46 (2H, m), 7.16 (2H, d,J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.67 (2H, d, J=8.4 Hz), 7.76 (2H, d,J=8.4 Hz), 8.66 (1H, t, J=6.0 Hz).

melting point: 124-126° C. (ethyl acetate-hexane)

FABMS (pos) 401 [M+H]⁺

EXAMPLE 114′-chloro-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide obtainedin Example 10.

¹H-NMR (DMSO-d₆) δ: 1.27 (3H, d, J=6.6 Hz), 1.64 (4H, m), 2.27 (2H, m),2.44 (2H, m), 2.83 (2H, m), 3.15 (1H, m), 3.49 (2H, m), 7.20 (4H, m),7.53 (2H, d, J=8.7 Hz), 7.75 (4H, m), 7.91 (2H, d, J=8.1 Hz), 8.62 (1H,t, J=5.4 Hz).

melting point: 152-153° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 433 [M+H]⁺

EXAMPLE 124′-methoxy-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide obtainedin Example 10.

¹H-NMR (DMSO-d₆) δ: 1.27 (3H, d, J=6.6 Hz), 1.64 (4H, m), 2.28 (2H, m),2.43 (2H, m), 2.83 (2H, m), 3.17 (1H, m), 3.52 (2H, m), 3.81 (3H, s),7.04 (2H, d, J=9.0 Hz), 7.24 (4H, m), 7.68 (4H, m), 7.88 (2H, d, J=8.4Hz), 8.58 (1H, t, J=6.0 Hz).

melting point: 163-165° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 429 [M+H]⁺

EXAMPLE 134′-fluoro-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide obtainedin Example 10.

¹H-NMR (DMSO-d6) δ: 1.27 (3H, d, J=6.6 Hz), 1.64 (4H, m), 2.28 (2H, m),2.42 (2H, m), 2.83 (2H, m), 3.16 (1H, m), 3.50 (2H, m), 7.15-7.36 (6H,m), 7.72-7.81 (4H, m), 7.92 (2H, d, J=8.4 Hz), 8.62 (1H, t, J=5.2 Hz).

melting point: 141-143° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 417 [M+H]⁺

EXAMPLE 144′-methyl-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide obtainedin Example 10.

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, d, J=6.6 Hz), 1.65 (4H, m), 2.29 (2H, m),2.35 (3H, s), 2.43 (2H, m), 2.83 (2H, m), 3.15 (1H, m), 3.50 (2H, m),7.16-7.26 (4H, m), 7.29 (2H, d, J=8.0 Hz), 7.62 (2H, d, J=8.0 Hz), 7.72(2H, d, J=8.4 Hz), 7.90 (2H, d, J=8.0 Hz), 8.60 (1H, m).

melting point: 160-163° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 413 [M+H]⁺

EXAMPLE 15N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)-4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide obtainedin Example 10.

¹H-NMR (DMSO-d₆) δ: 1.27 (3H, d, J=6.3 Hz), 1.64 (4H, m), 2.27 (2H, m),2.44 (2H, m), 2.84 (2H_(,) m), 3.15 (1H, m), 3.50 (2H, m), 7.17 (2H, d,J=8.1 Hz), 7.23 (2H, d, J=8.1 Hz), 7.84 (4H, m), 7.95 (4H, m), 8.66 (1H,t, J=5.7 Hz).

melting point: 149-151° C. (ethyl acetate-isopropyl ether-hexane)

FABMS (pos) 467 [M+H]⁺

EXAMPLE 16N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)-4′-(trifluoromethoxy)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide obtainedin Example 10.

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, d, J=6.6 Hz), 1.65 (4H, m), 2.29 (2H, m),2.43 (2H, m), 2.83 (2H, m), 3.17 (1H, m), 3.50 (2H, m), 7.18 (2H, d,J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.48 (2H, d, J=8.4 Hz), 7.78 (2H, d,J=8.4 Hz), 7.86 (2H, d, J=8.4 Hz), 7.93 (2H, d, J=8.4 Hz), 8.65 (1H, t,J=5.4 Hz).

melting point: 135-137° C. (ethyl acetate-isopropyl ether-hexane)

FABMS (pos) 483 [M+H]⁺

EXAMPLE 176-(4-methoxyphenyl)-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}nicotinamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 1.79 (4H, m), 2.51 (4H, m), 2.94 (2H, t, J=6.8 Hz),3.60 (2H, s), 3.75 (2H, q, J 6.6 Hz), 3.87 (3H, s), 6.14 (1H, t, J=5.9Hz), 7.01 (2H, m), 7.19 (2H, d, J=8.1 Hz), 7.31 (2H, d, J=8.1 Hz), 7.72(1H, d, J=8.4 Hz), 7.99 (2H, m), 8.07 (1H, dd, J=8.2, 2.4 Hz), 8.87 (1H,d, J=1.8 Hz).

melting point: 177-178° C. (ethyl acetate-isopropyl ether)

EXAMPLE 184′-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 1.79 (4H, m), 2.51 (4H, m), 2.93 (2H, t, j =6.8 Hz),3.59 (2H, s), 3.73 (2H, q, J=6.7 Hz), 6.13 (1H, t, J=5.5 Hz), 7.13 (2H,m), 7.19 (2H, d, J=8.1 Hz), 7.29 (2H, m), 7.55 (4H, m), 7.74 (2H, d,J=8.6 Hz).

melting point: 178-179° C. (ethyl acetate-isopropyl ether)

EXAMPLE 194-(benzyloxy)-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 1.79 (4H, m), 2.50 (4H, m), 2.90 (2H, t, J=6.8 Hz),3.59 (2H, s), 3.69 (2H, q, J=6.7 Hz), 5.09 (2H, s), 6.00 (1H, t, J=5.6Hz), 6.95 (2H, m), 7.17 (2H, d, J=8.1 Hz), 7.28 (2H, m), 7.37 (5H, m),7.63 (2H, d, J=9.4 Hz).

melting point: 131° C. (ethyl acetate-isopropyl ether)

EXAMPLE 202-fluoro-4-(3-methylbutoxy)-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.68 (2H, m), 1.79 (5H, m),2.50 (4H, m), 2.90 (2H, t, J=6.8 Hz), 3.59 (2H, s), 3.71 (2H, m), 4.00(2H, t, J=6.6 Hz), 6.55 (1H, dd, J=14.2, 2.2 Hz), 6.66 (1H, m), 6.75(1H, dd, J=8.8, 2.4 Hz), 7.17 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz),8.02 (1H, t, J=9.2 Hz).

melting point: 86-87° C. (ethyl acetate-isopropyl ether)

EXAMPLE 213,4′-difluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamineobtained in Reference Example 4.

¹H-NMR (CDCl₃) δ: 1.78 (4H, m), 2.50 (4H, m), 2.94 (2H, t, J=7.0 Hz),3.60 (2H, s), 3.75 (2H, m), 6.79 (1H, m), 7.20 (8H, m), 7.43 (1H, dd,J=8.1, 1.8 Hz), 7.55 (2H, m).

melting point: 139-140° C. (ethyl acetate-isopropyl ether)

EXAMPLE 22 4-butoxy-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 0.98 (3H, t, J=7.3 Hz), 1.49 (2H, m), 1.78 (6H, m),2.50 (4H, m), 2.90 (2H, t, J=6.7 Hz), 3.59 (2H, s), 3.69 (2H, m), 3.99(2H, t, J=6.5 Hz), 6.02 (1H, t, J=5.8 Hz), 6.88 (2H, m), 7.18 (2H, d,J=8.3 Hz), 7.29 (2H, m), 7.63 (2H, m).

melting point: 114° C. (ethyl acetate-isopropyl ether)

EXAMPLE 233′-isobutyrylamino-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamineobtained in Reference Example 4.

¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=6.9 Hz), 1.78 (4H, m), 2.53 (5H, m),2.94 (2H, t, J=6.7 Hz), 3.60 (2H, s), 3.73 (2H, q, J=6.6 Hz), 6.16 (1H,t, J=5.6 Hz), 7.20 (2H, d, J=8.3 Hz), 7.30 (3H, m), 7.34 (1H, t, J=1.5Hz), 7.40 (1H, t, J=7.7 Hz), 7.49 (1H, m), 7.62 (2H, m), 7.73 (2H, m),7.89 (1H, s).

melting point: 185-186° C. (ethyl acetate-isopropyl ether)

EXAMPLE 244-(2-oxo-2-phenylethyl)-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 1.78 (4H, m), 2.51 (4H, m), 2.91 (2H, t, J=6.9 Hz),3.60 (2H, s), 3.70 (2H, m), 4.32 (2H, s), 6.08 (1H, t, J=5.9 Hz), 7.18(2H, d, J=8.0 Hz), 7.29 (4H, m), 7.46 (2H, m), 7.58 (1H, m), 7.65 (2H,d, J=8.5 Hz), 8.00 (2H, m).

melting point: 148° C. (ethyl acetate-isopropyl ether)

EXAMPLE 25N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}-4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamineobtained in Reference Example 4.

¹H-NMR (CDCl₃) δ: 1.78 (4H, m), 2.51 (4H, m), 2.94 (2H, t, J=6.8 Hz),3.60 (2H, s), 3.74 (2H, m), 6.13 (1H, t, J=5.0 Hz), 7.19 (2H, d, J=8.1Hz), 7.30 (2H, m), 7.62 (2H, m), 7.70 (4H, m), 7.77 (2H, d, J=8.6 Hz).

melting point: 185-186° C. (ethyl acetate-isopropyl ether)

EXAMPLE 26N-(2-{4-[(dimethylamino)methyl]phenyl}ethyl)-4′-methoxy[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using N-[4-(2-aminoethyl)benzyl]-N,N-dimethylamine trifluoroacetateobtained in Reference Example 5.

¹H-NMR (CDCl₃) δ: 2.24 (6H, s), 2.94 (2H, t, J=6.8 Hz), 3.40 (2H, s),3.73 (2H, q, J=6.8 Hz), 3.85 (3H, s), 6.13 (1H, t, J=6.1 Hz), 6.98 (2H,m), 7.20 (2H, d, J=8.3 Hz), 7.26 (2H, m), 7.55 (4H, m), 7.72 (2H, d,J=8.5 Hz).

melting point: 197° C. (ethyl acetate-isopropyl ether)

EXAMPLE 274′-chloro-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-piperidinylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 6.

¹H-NMR (CDCl₃) δ: 1.43 (2H, m), 1.56 (4H, m), 2.37 (4H, m), 2.94 (2H, t,J=6.8 Hz), 3.45 (2H, s), 3.74 (2H, m), 6.15 (1H, t, J=5.7 Hz), 7.19 (2H,m), 7.28 (2H, m), 7.42 (2H, m), 7.53 (2H, m), 7.58 (2H, m), 7.76 (2H, d,J=8.4 Hz).

melting point: 176° C. (ethyl acetate-isopropyl ether)

EXAMPLE 284′-chloro-N-(2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethylaminetrihydrochloride obtained in Reference Example 7.

¹H-NMR (CDCl₃) δ: 2.28 (3H, s), 2.46 (8H, m), 2.94 (2H, t, J=7.0 Hz),3.50 (2H, s), 3.73 (2H, m), 6.16 (1H, t, J=5.9 Hz), 7.19 (2H, d, J=8.1Hz), 7.29 (2H, m), 7.50 (6H, m), 7.76 (2H, m).

melting point: 177° C. (ethyl acetate-isopropyl ether)

EXAMPLE 294′-fluoro-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-piperidinylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 6.

¹H-NMR (CDCl₃) δ: 1.43 (2H, m), 1.57 (4H, m), 2.37 (4H, m), 2.94 (2H, t,J=6.9 Hz), 3.45 (2H, s), 3.74 (2H, m), 6.15 (1H, t, J=5.6 Hz), 7.15 (4H,m), 7.29 (2H, m), 7.56 (4H, m), 7.75 (2H, m).

melting point: 175° C. (ethyl acetate-isopropyl ether)

EXAMPLE 304′-fluoro-N-(2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}ethylaminetrihydrochloride obtained in Reference Example 7.

¹H-NMR (CDCl₃) δ: 2.28 (3H, s), 2.47 (8H, m), 2.94 (2H, t, J=6.9 Hz),3.50 (2H, s), 3.74 (2H, m), 6.14 (1H, t, J=5.6 Hz), 7.14 (2H, m) 7.20(2H, d, J=8.3 Hz), 7.29 (2H, m), 7.56 (4H, m), 7.76 (2H, d, J=8.5 Hz).

melting point: 170° C. (ethyl acetate-isopropyl ether)

EXAMPLE 31N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide obtainedin Example 10.

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, d, J=6.6 Hz), 1.65 (4H, m), 2.28 (2H, m),2.45 (2H, m), 2.84 (2H, m), 3.16 (1H, m), 3.50 (2H, m), 7.18 (2H, d,J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.41 (1H, m), 7.50 (2H, m), 7.73 (2H,d, J=8.4 Hz), 7.76 (2H, d, J=8.4 Hz), 7.92 (2H, d, J=8.4 Hz), 8.64 (1H,t, J=5.7 Hz).

melting point: 136-138° C. (ethyl acetate-isopropyl ether-hexane)

FABMS (pos) 399 [M+H]⁺

EXAMPLE 324-bromo-N-(2-{4-[1-(1-pyrrolidinyl)propyl]phenyl}ethyl)benzamide

The title compound was obtained by similar operations as in ReferenceExample 19-21 and Example 10 and using4-bromo-N-(2-phenylethyl)benzamide.

¹H-NMR (DMSO-d₆) δ: 0.59 (3H, t, J=7.5 Hz), 1.63 (5H, m), 1.85 (1H, m),2.27 (2H, m), 2.49 (2H, m), 2.79 (2H, m), 2.99 (1H, m), 3.47 (2H, m),7.17 (4H, m), 7.66 (2H, d, J=8.7 Hz), 7.75 (2H, d, J=8.7 Hz), 8.65 (1H,m).

melting point: 90-92° C. (ethyl acetate-isopropyl ether-hexane)

FABMS (pos) 415 [M+H]⁺

EXAMPLE 334′-chloro-N-(2-{4-[1-(1-pyrrolidinyl)propyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-(2-{4-[1-(1-pyrrolidinyl)propyl]phenyl}ethyl)benzamideobtained in Example 32.

¹H-NMR (DMSO-d₆) δ: 0.60 (3H, t, J=7.5 Hz), 1.63 (5H, m), 1.85 (1H, m),2.27 (2H, m), 2.43 (2H, m), 2.84 (2H, m), 2.98 (1H, m), 3.50 (2H, m),7.16 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=7.6 Hz), 7.55 (2H, d, J=8.4 Hz),7.77 (4H, m), 7.92 (2H, d, J=8.4 Hz), 8.62 (1H, m).

melting point: 151-153° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 447 [M+H]⁺

EXAMPLE 344′-chloro-N-[2-(4-{1-[(2R,6S)-2,6-dimethyl-1-piperidinyl]ethyl}phenyl)ethyl][1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 10and Example 6 and using4-bromo-N-{2-[4-(1-chloroethyl)phenyl]ethyl}benzamide obtained inReference Example 21.

¹H-NMR (DMSO-d₆) δ: 0.69 (3H, d, J=6.6 Hz), 1.08 (3H, d, J=6.6 Hz), 1.27(3H, d, J=6.6 Hz), 1.44-1.61 (6H, m), 2.57 (1H, m), 2.82 (2H, m), 3.02(1H, m), 3.50 (2H, m), 4.02 (1H, m), 7.17 (2H, d, J=8.4 Hz), 7.33 (2H,d, J=7.6 Hz), 7.55 (2H, d, J=8.4 Hz), 7.77 (4H, m), 7.92 (2H, d, J=8.4Hz), 8.62 (1H, m).

melting point: 137-139° C. (ethyl acetate-isopropyl ether-hexane)

EXAMPLE 354′-chloro-N-[2-(4-{1-[3-(methylsulfonyl)-1-pyrrolidinyl]ethyl}phenyl)ethyl][1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 10and Example 6 and using4-bromo-N-{2-[4-(1-chloroethyl)phenyl]ethyl}benzamide obtained inReference Example 21.

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, d, J=6.6 Hz), 2.07 (2H, m), 2.37 (1H, m),2.62-2.87 (5H, m), 2.89, 2.90 (3H, sx2), 3.26 (1H, m), 3.51 (2H, m),3.70 (1H, m), 7.21 (4H, m), 7.53 (2H, d, J=8.7 Hz), 7.76 (4H, m), 7.91(2H, d, J=8.1 Hz), 8.63 (1H, t, J=5.4 Hz).

Elemental analysis for C₂₈H₃₁ClN₂O₃S

Calculated: C, 65.80; H, 6.11; N, 5.48.

Found: C, 65.66; H, 6.13; N, 5.39.

FABMS (pos) 511 [M+H]⁺

EXAMPLE 364′-chloro-N-(2-{4-[2-methyl-1-(1-pyrrolidinyl)propyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in ReferenceExample 19-21, Example 10 and Example 6 and using4-bromo-N-(2-phenylethyl)benzamide.

¹H-NMR (DMSO-d₆) δ: 0.71 (6H, m), 1.62 (4H, m), 2.15 (1H, m), 2.30-2.35(4H, m), 2.84 (2H, m), 2.98 (1H, m), 3.50 (2H, m), 7.15 (4H, m), 7.55(2H, d, J=9.0 Hz), 7.77 (4H, m), 7.91 (2H, d, J=8.7 Hz), 8.65 (1H, t,J=5.7 Hz).

melting point: 143-145° C. (ethyl acetate-isopropyl ether-hexane)

FABMS (pos) 461 [M+H]⁺

EXAMPLE 374′-chloro-N-(2-{4-[1-(4-thiomorpholinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 10and Example 6 and using4-bromo-N-{2-[4-(1-chloroethyl)phenyl]ethyl}benzamide obtained inReference Example 21.

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, d, J=6.9 Hz), 2.56 (4H, m), 2.59 (4H, m),2.84 (2H, m), 3.49 (2H, m), 3.57 (1H, m), 7.20 (4H, m), 7.54 (2H, d,J=8.4 Hz), 7.74 (4H, m), 7.91 (2H, d, J=8.7 Hz), 8.63 (1H, t, J=5.7 Hz).

melting point: 168-169° C. (ethyl acetate-isopropyl ether-hexane)

FABMS (pos) 465 [M+H]⁺

EXAMPLE 384-pentyl-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine obtained inReference Example 14.

¹H-NMR (CDCl₃) δ: 0.88 (3H, t, J=6.3 Hz), 1.31 (4H, m), 1.40 (3H, d,J=6.6 Hz), 1.61 (2H, t, J=8.1 Hz), 1.76 (4H, m), 2.38 (2H, m), 2.55 (2H,m), 2.63 (2H, t, J=7.1 Hz), 2.91 (2H, t, J=6.9 Hz), 3.18 (1H, q, J=6.6Hz), 3.70 (2H, q, J=6.9 Hz), 6.09 (1H, m), 7.18 (4H, m), 7.28 (2H, m),7.59 (2H, d, J=8.1 Hz).

melting point: 76-77° C. (ethyl acetate-hexane)

ESIMS (pos) 393 [M+H]⁺

EXAMPLE 394-butoxy-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine obtained inReference Example 14.

¹H-NMR (CDCl₃) δ: 0.98 (3H, t, J=7.2 Hz), 1.40 (3H, d, J=6.6 Hz), 1.48(2H, m), 1.73 (6H, m), 2.36 (2H, m), 2.57 (2H, m), 2.90 (2H, t, J=6.6Hz), 3.18 (1H, q, J=6.3 Hz), 3.71 (2H, q, J=7.2 Hz), 3.99 (2H, t, J=6.6Hz), 6.04 (1H, m), 6.87 (2H, d, J=8.7 Hz), 7.17 (2H, d, J=7.8 Hz), 7.29(2H, d, J=8.1 Hz), 7.63 (2H, d, J=8.7 Hz).

melting point: 99-100° C. (ethyl acetate-hexane)

EXAMPLE 404-cyclopropylmethoxy-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine obtained inReference Example 14.

¹H-NMR (CDCl₃) δ: 0.35 (2H, m), 0.64 (2H, m), 1.28 (1H, m), 1.40 (3H, d,J=6.6 Hz), 1.76 (4H, m), 2.39 (2H, m), 2.54 (2H, m), 2.90 (2H, t, J=6.6Hz), 3.18 (1H, q, J=6.6 Hz), 3.69 (2H, q, J=6.6 Hz), 3.83 (2H, d, J=7.0Hz), 6.04 (1H, m), 6.88 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=7.8 Hz), 7.29(2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.8 Hz).

melting point: 122-123° C. (ethyl acetate-hexane)

EXAMPLE 414-benzyloxy-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine obtained inReference Example 14.

¹H-NMR (CDCl₃) δ: 1.39 (3H, d, J=6.6 Hz), 1.76 (4H, m), 2.36 (2H, m),2.54 (2H, m), 2.90 (2H, t, J=7.0 Hz), 3.16 (1H, q, J=6.2 Hz), 3.69 (2H,q, J=6.2 Hz), 5.10 (2H, s), 6.03 (1H, m), 6.96 (2H, d, J=8.8 Hz), 7.16(2H, d, J=8.0 Hz), 7.26-7.41 (7H, m), 7.64 (2H, d, J=8.8 Hz).

melting point: 132-133° C. (ethyl acetate-hexane)

EXAMPLE 424-(2-oxo-2-phenylethyl)-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine obtained inReference Example 14.

¹H-NMR (CDCl₃) δ: 1.53 (3H, d, J=7.0 Hz), 1.84 (4H, m), 2.60 (2H, m),2.79 (2H, m), 2.92 (2H, t, J=7.0 Hz), 3.46 (1H, q, J=7.0 Hz), 3.69 (2H,q, J=7.0 Hz), 4.32 (2H, s), 6.30 (1H, m), 7.18-7.68 (11H, m), 8.00 (2H,d, J=8.8 Hz).

melting point: 123-124° C. (ethyl acetate-hexane)

EXAMPLE 432-fluoro-4-(3-methyl-2-oxobutyl)-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine obtained inReference Example 14.

¹H-NMR (CDCl₃) δ: 1.12 (6H, d, J=6.9 Hz), 1.39 (3H, d, J=6.6 Hz), 1.76(4H, m), 2.36 (2H, m), 2.52 (2H, m), 2.71 (1H, m), 2.90 (2H, t, J=7.2Hz), 3.17 (1H, q, J=6.6 Hz), 3.71 (2H, q, J=6.6 Hz), 3.77 (2H, s), 6.72(1H, m), 6.93 (1H, d, J=12.9 Hz), 7.05 (1H, d, J=8.1 Hz), 7.16 (2H, d,J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz), 8.02 (1H, t, J=8.1 Hz).

melting point: 97-98° C. (ethyl acetate-hexane)

EXAMPLE 44N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)-4-pentylbenzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 16.

¹H-NMR (CDCl₃) δ: 0.85, 1.10 (3H, d×2, J=6.6 Hz), 0.89 (3H, m), 1.25(6H, m), 1.37, 1.47 (3H, d×2, J=6.6 Hz), 1.39-1.52 (2H, m), 1.62-1.87(4H, m), 2.38-2.59 (2H, m), 2.77 (1H, m), 2.90 (2H, m), 3.70 (2H, m),3.85 (1H, m), 6.12 (1H, m), 7.13-7.38 (6H, m), 7.62 (2H, m).

FABMS (pos) 407 [M+H]⁺

EXAMPLE 454-butoxy-N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 16.

¹H-NMR (CDCl₃) δ: 0.85, 1.10 (3H, d×2, J=6.6 Hz), 0.97 (3H, t, J=7.4Hz), 1.37, 1.47 (3H, d×2, J=6.6 Hz), 1.39-1.52 (2H, m), 1.62-1.87 (6H,m), 2.38-2.59 (2H, m), 2.77 (1H, m), 2.90 (2H, m), 3.70 (2H, m), 3.85(1H, m), 3.96 (2H, t, J=6.6 Hz), 6.14 (1H, m), 6.86 (2H, m), 7.10-7.34(4H, m), 7.64 (2H, m).

FABMS (pos) 409 [M+H]⁺

EXAMPLE 464-(4-methyl-2-oxopentyl)-N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 16.

¹H-NMR (CDCl₃) δ: 0.84, 1.09 (3H, d×2, J=6.6 Hz), 0.88 (7H, m), 1.37,1.45 (3H, d×2, J=6.6 Hz), 1.59-2.16 (4H, m), 2.31-2.58 (4H, m), 2.74(1H, m), 2.88 (2H, m), 3.74 (4H, m), 3.86 (1H, m), 6.29 (1H, m),7.14-7.43 (6H, m), 7.65 (2H, m).

FABMS (pos) 435 [M+H]⁺

EXAMPLE 47 4-benzyloxy-N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 16.

¹H-NMR (CDCl₃) δ: 0.85, 1.09 (3H, d×2, J=6.6 Hz), 1.33, 1.45 (3H, d×2,J=6.6 Hz), 1.62-1.87 (4H, m), 2.36-2.54 (2H, m), 2.74 (1H, m), 2.89 (2H,m), 3.68 (2H, m), 3.85 (1H, m), 5.08 (2H, s), 6.14 (1H, m), 6.95 (2H,m), 7.18-7.43 (9H, m), 7.67 (2H, m).

FABMS (pos) 443 [M+H]⁺

EXAMPLE 48N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)-4-(2-oxo-2-phenylethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 16.

¹H-NMR (CDCl₃) δ: 0.83, 1.09 (3H, d×2, J=6.3 Hz), 1.35, 1.44 (3H, d×2,J=6.6 Hz), 1.53-1.90 (4H, m), 2.35-2.56 (2H, m), 2.74 (1H, m), 2.90 (2H,m), 3.70 (2H, m), 3.79 (1H, m), 4.31 (2H, s), 6.31 (1H, m), 7.13-7.68(11H, m), 8.00 (2H, m).

FABMS (pos) 455 [M+H]⁺

EXAMPLE 494-cyclopropylmethoxy-N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 16.

¹H-NMR (CDCl₃) δ: 0.34 (2H, m), 0.64 (2H, m), 0.84, 1.08 (3H, d×2, J=6.6Hz), 1.25 (1H, m), 1.35, 1.42 (3H, d×2, J=6.6 Hz), 1.53-1.94 (4H, m),2.33-2.55 (2H, m), 2.73 (1H, m), 2.89 (2H, m.), 3.68 (3H, m), 3.82 (2H,d, J=6.3 Hz), 6.27 (1H, m), 6.85 (2H, m), 7.17 (3H, m), 7.28 (1H, m),7.65 (2H, m).

FABMS (pos) 407 [M+H]⁺

EXAMPLE 504′-chloro-N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 16.

¹H-NMR (CDCl₃) δ: 0.85, 1.10 (3H, d×2, J=6.6 Hz), 1.35, 1.46 (3H, d×2,J=6.6 Hz), 1.55-1.92 (4H, m), 2.35-2.56 (2H, m), 2.76 (1H, m), 2.90 (2H,m), 3.73 (2H, m), 3.85 (1H, q, J=6.9 Hz), 6.37 (1H, m), 7.18 (2H, m),7.47-7.55 (8H, m), 7.76 (2H, m).

FABMS (pos) 447 [M+H]⁺

EXAMPLE 514′-fluoro-N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 16.

¹H-NMR (CDCl₃) δ: 0.87, 1.11 (3H, d×2, J=6.6 Hz), 1.39, 1.47 (3H, d×2,J=6.6 Hz), 1.58-1.90 (4H, m), 2.45-2.58 (2H, m), 2.83 (1H, m), 2.92 (2H,m), 3.74 (2H, m), 3.90 (1H, q, J=6.9 Hz), 6.23 (1H, m), 7.10-7.45 (6H,m), 7.59 (4H, m), 7.76 (2H, m).

FABMS (pos) 431 [M+H]⁺

EXAMPLE 52N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)-4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamine obtained inReference Example 16.

¹H-NMR (CDCl₃) δ: 0.86, 1.10 (3H, d×2, J=6.6 Hz), 1.35, 1.45 (3H, d×2,J=6.6 Hz), 1.54-2.00 (4H, m), 2.36-2.57 (2H, m), 2.73 (1H, m), 2.93 (2H,m), 3.74 (2H, m), 3.90 (1H, q, J=6.9 Hz), 6.44 (1H, m), 7.20-7.79 (10H,m), 7.76 (2H, m).

FABMS (pos) 481 [M+H]⁺

EXAMPLE 534′-methoxy-N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 16.

¹H-NMR (CDCl₃) δ: 0.86, 1.10 (3H, d×2, J=6.6 Hz), 1.35, 1.46 (3H, d×2,J=6.6 Hz), 1.56-2.04 (4H, m), 2.41-2.53 (2H, m), 2.75 (1H, m), 2.92 (2H,m), 3.75 (3H, m), 3.85 (3H, s), 6.31 (1H, m), 6.76 (2H, m), 6.96 (2H,m), 7.20 (2H, m), 7.40-7.54 (4H, m), 7.73 (2H, m).

FABMS (pos) 443 [M+H]⁺

EXAMPLE 54N-(2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethyl)-4′-(trifluoromethoxy)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using2-{4-[1-(2-methyl-1-pyrrolidinyl)ethyl]phenyl}ethylamine obtained inReference Example 16.

¹H-NMR (CDCl₃) δ: 0.85, 1.10 (3H, d×2, J=6.6 Hz), 1.36, 1.44 (3H, d×2,J=6.6 Hz), 1.59-2.07 (4H, m), 2.37-2.54 (2H, m), 2.77 (1H, m), 2.93 (2H,m), 3.75 (2H, .m), 3.84 (1H, q, J=6.9 Hz), 6.15 (1H, m), 7.15-7.32 (6H,m), 7.59 (4H, m), 7.76 (2H, m).

FABMS (pos) 497 [M+H]⁺

EXAMPLE 554′-chloro-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.6 Hz), 1.38 (2H, m), 1.55 (4H, m),2.36 (4H, m), 2.94 (2H, t, J=6.6 Hz), 3.39 (1H, q, J=6.6 Hz), 3.73 (2H,q, J=6.6 Hz), 6.16 (1H, m), 7.17-7.27 (4H, m), 7.41 (2H, d, J=8.0 Hz),7.51 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.0 Hz), 7.75 (2H, d, J=7.8 Hz).

melting point: 152-153° C. (ethyl acetate-hexane)

EXAMPLE 564′-fluoro-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.6 Hz), 1.38 (2H, m), 1.54 (4H, m),2.35 (4H, m), 2.93 (2H, t, J=6.6 Hz), 3.39 (1H, q, J=7.2 Hz), 3.73 (2H,q, J=6.0 Hz), 6.15 (1H, m), 7.10-7.27 (6H, m), 7.55 (4H, m), 7.75 (2H,d, J=8.0 Hz).

melting point: 133-134° C. (ethyl acetate-hexane)

EXAMPLE 574′-methoxy-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.9 Hz), 1.38 (2H, m), 1.55 (4H, m),2.35 (4H, m), 2.93 (2H, t, J=6.6 Hz), 3.39 (1H, q, J=6.6 Hz), 3.74 (2H,q, J=6.3 Hz), 3.85 (3H, s), 6.14 (1H, m), 6.97 (2H, d, J=8.7 Hz),7.17-7.27 (4H, m), 7.52-7.59 (4H, m), 7.72 (2H, d, J=8.1 Hz).

melting point: 156-157° C. (ethyl acetate-hexane)

EXAMPLE 584′-methyl-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.9 Hz), 1.38 (2H, m) 1.53 (4H, m),2.34 (4H, m), 2.41 (3H, s), 2.93 (2H, t, J=6.9 Hz), 3.37 (1H, q, J=6.6Hz), 3.73 (2H, q, J=6.6 Hz), 6.15 (1H, m), 7.17 (2H, d, J=8.1 Hz), 7.25(4H, m), 7.49 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.72 (2H, d,J=8.4 Hz).

melting point: 172-173° C. (ethyl acetate-hexane)

EXAMPLE 59N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.6 Hz), 1.38 (2H, m), 1.54 (4H, m),2.34 (4H, m), 2.94 (2H, t, J=6.8 Hz), 3.39 (1H, q, J=6.6 Hz), 3.73 (2H,q, J=6.6 Hz), 6.16 (1H, m), 7.17-7.37 (4H, m), 7.37-7.47 (3H, m), 7.60(4H, m), 7.74 (2H, d, J=8.4 Hz).

melting point: 136-137° C. (ethyl acetate-hexane)

EXAMPLE 60N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)-4′-(trifluoromethoxy)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 15.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.6 Hz), 1.38 (2H, m), 1.55 (4H, m),2.35 (4H, m), 2.94 (2H, t, J=6.9 Hz), 3.39 (1H, q, J=6.6 Hz), 3.74 (2H,q, J=6.6 Hz), 6.17 (1H, m), 7.17 (2H, d, J=8.1 Hz), 7.27 (4H, m), 7.59(4H, m), 7.75 (2H, d, J=8.1 Hz).

melting point: 138-139° C. (ethyl acetate-hexane)

EXAMPLE 61N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)-4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 15.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.6 Hz), 1.38 (2H, m), 1.57 (4H, m),2.35 (4H, m), 2.94 (2H, t, J=6.9 Hz), 3.40 (1H, q, J=6.6 Hz), 3.74 (2H,q, J=6.6 Hz), 6.16 (1H, m), 7.18 (2H, d, J=8.4 Hz), 7.20 (2H, m),7.61-7.73 (6H, m), 7.75 (2H, d, J=8.4 Hz).

melting point: 150-152° C. (ethyl acetate-hexane)

EXAMPLE 624-benzyloxy-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.8 Hz), 1.38 (2H, m), 1.53 (4H, m),2.34 (4H, m), 2.90 (2H, t, J=6.8 Hz), 3.38 (1H, q, J=6.8 Hz), 3.69 (2H,q, J=6.2 Hz), 5.09 (2H, s), 6.02 (1H, m), 6.95 (2H, d, J=8.4 Hz),7.15-7.40 (9H, m), 7.62 (2H, d, J=8.6 Hz).

melting point: 124-125° C. (ethyl acetate-hexane)

EXAMPLE 634-cyclopropylmethoxy-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 0.34 (2H, m), 0.65 (2H, m), 1.25 (1H, m), 1.35 (3H, d,J=6.8 Hz), 1.38 (2H, m), 1.53 (4H, m), 2.34 (4H, m), 2.90 (2H, t, J=6.8Hz), 3.38 (1H, q, J=6.6 Hz), 3.68 (2H, q, J=6.6 Hz), 3.82 (2H, d, J=6.8Hz), 6.03 (1H, m), 6.87 (2H, d, J=9.0 Hz), 7.16 (2H, d, J=7.8 Hz), 7.23(2H, d, J=7.8 Hz), 7.62 (2H, d, J=8.8 Hz).

melting point: 141-142° C. (ethyl acetate-hexane)

EXAMPLE 644-(2-cyclopropylethoxy)-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 0.11 (2H, m), 0.48 (2H, m), 0.85 (1H, m), 1.35 (3H, d,J=6.6 Hz), 1.38 (2H, m), 1.55 (4H, m), 1.75 (2H, q, J=6.6 Hz), 2.36 (4H,m), 2.90 (2H, t, J=6.8 Hz), 3.40 (1H, q, J=6.8 Hz), 3.68 (2H, q, J=6.6Hz), 4.05 (2H, d, J=6.6 Hz), 6.04 (1H, m), 6.88 (2H, d, J=8.8 Hz), 7.16(2H, d, J=7.2 Hz), 7.23 (2H, d, J=7.2 Hz), 7.63 (2H, d, J=8.8 Hz).

melting point: 125-126° C. (ethyl acetate-hexane)

EXAMPLE 654-isobutoxy-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.36 (3H, d, J=6.8 Hz), 1.38(2H, m), 1.55 (4H, m), 2.09 (1H, m), 2.34 (4H, m), 2.90 (2H, t, J=7.2Hz), 3.39 (1H, q, J=6.8 Hz), 3.68 (2H, q, J=6.6 Hz), 3.73 (2H, d, J=6.6Hz), 6.03 (1H, m), 6.88 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=7.8 Hz), 7.23(2H, d, J=7.8 Hz), 7.62 (2H, d, J=8.8 Hz).

melting point: 93-94° C. (ethyl acetate-hexane)

EXAMPLE 664-isopentyloxy-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 0.95 (6H, d, J=6.6 Hz), 1.35 (3H, d, J=6.8 Hz), 1.38(2H, m), 1.53 (4H, m), 1.71 (2H, m), 1.83 (1H, m), 2.34 (4H, m), 2.90(2H, t, J=6.8 Hz), 3.38 (1H, q, J=6.6 Hz), 3.69 (2H, q, J=6.6 Hz), 4.00(2H, t, J=6.6 Hz), 6.03 (1H, m), 6.86 (2H, d, J=8.6 Hz), 7.16 (2H, d,J=7.8 Hz), 7.31 (2H, d, J=7.8 Hz), 7.62 (2H, d, J=8.6 Hz).

melting point: 91-92° C. (ethyl acetate-hexane)

EXAMPLE 67N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4′-chloro[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine obtained inReference Example 17.

¹H-NMR (CDCl₃) δ: 1.34 (3H, d, J=6.6 Hz), 1.57 (8H, m), 2.62 (4H, m),2.93 (2H, t, J=6.9 Hz), 3.75 (3H, m), 6.15 (1H, m), 7.17 (2H, d, J=7.8Hz), 7.32 (2H, d, J=8.1 Hz), 7.41 (2H, d, J=8.1 Hz), 7.52 (2H, d, J=8.1Hz), 7.56 (2H, d, J=8.1 Hz), 7.74 (2H, d, J=8.1 Hz).

melting point: 147-148° C. (ethyl acetate-hexane)

EXAMPLE 68N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4′-fluoro[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine obtained inReference Example 17.

¹H-NMR (CDCl₃) δ: 1.34 (3H, d, J=6.6 Hz), 1.57 (8H, m), 2.61 (4H, m),2.93 (2H, t, J=6.6 Hz), 3.75 (3H, m), 6.15 (1H, m), 7.10-7.25 (4H, m),7.32 (2H, d, J=8.1 Hz), 7.54 (4H, m), 7.74 (2H, d, J=8.4 Hz).

melting point: 128-129° C. (ethyl acetate-hexane)

EXAMPLE 69N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4′-methoxy[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine obtained inReference Example 17.

¹H-NMR (CDCl₃) δ: 1.35 (3H, d, J=6.6 Hz), 1.58 (8H, m), 2.62 (4H, m),2.93 (2H, t, J=7.0 Hz), 3.72 (3H, m), 3.86 (3H, s), 6.14 (1H, m), 6.99(2H, d, J=8.8 Hz), 7.16-7.35 (4H, m), 7.56 (4H, m), 7.73 (2H, d, J=8.0Hz).

melting point: 136-137° C. (ethyl acetate-hexane)

EXAMPLE 70N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4′-methyl[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine obtained inReference Example 17.

¹H-NMR (CDCl₃) δ: 1.35 (3H, d, J=6.6 Hz), 1.57 (8H, m), 2.40 (3H, s),2.61 (4H, m), 2.93 (2H, t, J=6.6 Hz), 3.74 (3H, m), 6.14 (1H, m),7.16-7.35 (6H, m), 7.49 (2H, d, J=8.2 Hz), 7.60 (2H, d, J=8.6 Hz), 7.73(2H, d, J=8.0 Hz).

melting point: 146-148° C. (ethyl acetate-hexane)

EXAMPLE 71N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2,and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine obtained inReference Example 17.

¹H-NMR (CDCl₃) δ: 1.34 (3H, d, J=6.6 Hz), 1.57 (8H, m), 2.62 (4H, m),2.94 (2H, t, J=6.6 Hz), 3.75 (3H, m), 6.18 (1H, m), 7.18-7.48 (7H, m),7.61 (4H, m), 7.76 (2H, d, J=8.4 Hz).

melting point: 104-105° C. (ethyl acetate-hexane)

EXAMPLE 72N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4′-(trifluoromethoxy)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamineobtained in Reference Example 17.

¹H-NMR (CDCl₃) δ: 1.35 (3H, d, J=6.6 Hz), 1.57 (8H, m), 2.62 (4H, m),2.93 (2H, t, J=6.6 Hz), 3.75 (3H, m), 6.16 (1H, m), 7.16-7.33 (6H, m),7.78 (4H, m), 7.74 (2H, d, J=8.1 Hz).

melting point: 97-99° C. (ethyl acetate-hexane)

EXAMPLE 73N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamineobtained in Reference Example 17.

¹H-NMR (CDCl₃) δ: 1.35 (3H, d, J=6.9 Hz), 1.57 (8H, m), 2.62 (4H, m),2.94 (2H, t, J=6.6 Hz), 3.75 (3H, m), 6.19 (1H, m), 7.17 (2H, d, J=8.1Hz), 7.32 (2H, d, J=8.1 Hz), 7.66 (6H, m), 7.77 (2H, d, J=8.1 Hz).

melting point: 107-109° C. (ethyl acetate-hexane)

EXAMPLE 74N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4-(benzyloxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine obtained inReference Example 17.

¹H-NMR (CDCl₃) δ: 1.34 (3H, d, J=6.4 Hz), 1.57 (8H, m), 2.61 (4H, m),2.90 (2H, t, J=6.6 Hz), 3.73 (3H, m), 5.10 (2H, s), 6.02 (1H, m), 6.90(2H, d, J=8.1 Hz), 7.14-7.40 (9H, m), 7.64 (2H, d, J=8.1 Hz).

melting point: 121-122° C. (ethyl acetate-hexane)

EXAMPLE 75N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4-(cyclopropylmethoxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine obtained inReference Example 17.

¹H-NMR (CDCl₃) δ: 0.37 (2H, m), 0.65 (2H, m), 1.27 (1H, m), 1.34 (3H, d,J=6.4 Hz), 1.57 (8H, m), 2.61 (4H, m), 2.90 (2H, t, J=7.0 Hz), 3.68 (3H,m), 3.82 (2H, d, J=7.0 Hz), 6.02 (1H, m), 6.88 (2H, d, J=8.8 Hz), 7.16(2H, d, J=8.0 Hz), 7.31 (2H, d, J=8.0 Hz), 7.63 (2H, d, J=8.8 Hz).

melting point: 95-96° C. (ethyl acetate-hexane)

EXAMPLE 76N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4-(2-cyclopropylethoxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine obtained inReference Example 17.

¹H-NMR (CDCl₃) δ: 0.11 (2H, m), 0.49 (2H, m), 0.84 (1H, m), 1.34 (3H, d,J=6.9 Hz), 1.57 (8H, m), 1.68 (2H, q, J=6.6 Hz), 2.61 (4H, m), 2.90 (2H,t, J=6.9 Hz), 3.75 (3H, m), 4.05 (2H, t, J=6.9 Hz), 6.01 (1H, m), 6.88(2H, d, J=8.7 Hz), 7.16 (2H, d, J=8.1 Hz), 7.31 (2H, d, J=7.8 Hz), 7.62(2H, d, J=8.7 Hz).

melting point: 87-88° C. (ethyl acetate-hexane)

EXAMPLE 77N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4-(isobutoxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine obtained inReference Example 17.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.33 (3H, d, J=6.8 Hz), 1.58(8H, m), 2.08 (1H, m), 2.61 (4H, m), 2.90 (2H, t, J=6.9 Hz), 3.72 (5H,m), 6.13 (1H, m), 6.88 (2H, d, J=8.7 Hz), 7.16 (2H, d, J=8.1 Hz), 7.30(2H, d, J=7.8 Hz), 7.64 (2H, d, J=8.7 Hz).

melting point: 76-77° C. (ethyl acetate-hexane)

EXAMPLE 78N-(2-{4-[1-(1-azepanyl)ethyl]phenyl}ethyl)-4-(isopentyloxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(1-azepanyl)ethyl]phenyl}ethylamine obtained inReference Example 17.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.35 (3H, d, J=6.9 Hz), 1.57(8H, m), 1.69 (2H, q, J=6.6 Hz), 1.83 (1H, m), 2.61 (4H, m), 2.90 (2H,t, J=6.3 Hz), 3.70 (3H, m), 4.00 (2H, t, J=6.6 Hz), 6.03 (1H, m), 6.87(2H, d, J=8.7 Hz), 7.15 (2H, d, J=7.8 Hz), 7.31 (2H, d, J=7.8 Hz), 7.62(2H, d, J=8.7 Hz).

melting point: 78-79° C. (ethyl acetate-hexane)

EXAMPLE 794′-methoxy-N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamineobtained in Reference Example 18.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.9 Hz), 2.25 (3H, s), 2.42 (8H, m),2.92 (2H, t, J=6.9 Hz), 3.35 (1H, q, J=6.9 Hz), 3.72 (2H, q, J=6.6 Hz),3.85 (3H, s), 6.15 (1H, m), 6.97 (2H, d, J=9.0 Hz), 7.22 (2H, d, J=8.1Hz), 7.26 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4Hz), 7.73 (2H, d, J=8.4 Hz).

melting point: 152-154° C. (ethyl acetate-hexane)

EXAMPLE 804′-methyl-N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamineobtained in Reference Example 18.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.6 Hz), 2.26 (3H, s), 2.40 (3H, s),2.42 (8H, m), 2.93 (2H, t, J=6.6 Hz), 3.35 (1H, q, J=6.9 Hz), 3.72 (2H,q, J=6.9 Hz), 6.15 (1H, m), 7.18 (2H, d, J=8.1 Hz), 7.25 (4H, m), 7.49(2H, d, J=8.1 Hz), 7.60 (2H, d, J=8.1 Hz), 7.73 (2H, d, J=8.1 Hz).

melting point: 165-167° C. (ethyl acetate-hexane)

EXAMPLE 814-benzyloxy-N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamineobtained in Reference Example 18.

¹H-NMR (CDCl₃) δ: 1.35 (3H, d, J=6.6 Hz), 2.56 (3H, s), 2.42 (8H, m),2.89 (2H, t, J=7.2 Hz), 3.34 (1H, q, J=6.6 Hz), 3.68 (2H, q, J=6.3 Hz),5.09 (2H, s), 6.05 (1H, m), 6.96 (2H, d, J=8.7 Hz), 7.16 (2H, d, J=8.1Hz), 7.24 (2H, d, J=7.8 Hz), 7.39 (5H, m), 7.65 (2H, d, J=8.4 Hz).

melting point: 129-130° C. (ethyl acetate-hexane)

EXAMPLE 824-cyclopropylmethoxy-N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamineobtained in Reference Example 18.

¹H-NMR (CDCl₃) δ: 0.34 (2H, m), 0.63 (2H, m), 1.26 (1H, m), 1.35 (3H, d,J=6.6 Hz), 2.26 (3H, s), 2.42. (8H, m), 2.92 (2H, t, J=6.9 Hz), 3.33(1H, q, J=6.6 Hz), 3.68 (2H, q, J=6.6 Hz), 3.82 (2H, d, J=6.9 Hz), 6.02(1H, m), 6.88 (2H, d, J=8.7 Hz), 7.16 (2H, d, J=8.1 Hz), 7.24 (2H, d,J=8.1 Hz), 7.63 (2H, d, J=8.4 Hz).

melting point: 117-119° C. (ethyl acetate-hexane)

EXAMPLE 834-(2-cyclopropylethoxy)-N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamineobtained in Reference Example 18.

¹H-NMR (CDCl₃) δ: 0.11 (2H, m), 0.49 (2H, m), 0.85 (1H, m), 1.35 (3H, d,J=6.6 Hz), 1.68 (2H, q, J=6.6 Hz), 2.26 (3H, s), 2.42 (8H, m), 2.90 (2H,t, J=6.6 Hz), 3.34 (1H, q, J=6.6 Hz), 3.68 (2H, q, J=6.6 Hz), 4.06 (2H,t, J=6.9 Hz), 6.04 (1H, m), 6.88 (2H, d, J=8.7 Hz), 7.16 (2H, d, J=8.1Hz), 7.25 (2H, d, J=8.1 Hz), 7.65 (2H, d, J=8.4 Hz).

melting point: 102-103° C. (ethyl acetate-hexane)

EXAMPLE 844-isobutoxy-N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamineobtained in Reference Example 18.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.35 (3H, d, J=6.9 Hz), 2.08(1H, m), 2.26 (3H, s), 2.42 (8H, m), 2.90 (2H, t, J=6.6 Hz), 3.34 (1H,q, J=6.6 Hz), 3.68 (2H, q, J=6.6 Hz), 3.73 (2H, d, J=6.6 Hz), 6.04 (1H,m), 6.87 (2H, d, J=8.4 Hz), 7.15 (2H, d, J=8.1 Hz), 7.25 (2H, d, J=7.8Hz), 7.64 (2H, d, J=8.4 Hz).

melting point: 92-93° C. (ethyl acetate-hexane)

EXAMPLE 854-isopentyloxy-N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamineobtained in Reference Example 18.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.35 (3H, d, J=6.6 Hz), 1.68(2H, q, J=6.6 Hz), 1.83 (1H, m), 2.26 (3H, s), 2.42 (8H, m), 2.90 (2H,t, J=6.9 Hz), 3.35 (1H, q, J=6.6 Hz), 3.69 (2H, q, J=6.6 Hz), 4.01 (2H,t, J=6.6 Hz), 6.04 (1H, m), 6.88 (2H, d, J=8.4 Hz), 7.15 (2H, d, J=7.8Hz), 7.26 (2H, d, J=7.8 Hz), 7.62 (2H, d, J=8.4 Hz).

melting point: 91-92° C. (ethyl acetate-hexane)

EXAMPLE 864-bromo-N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamineobtained in Reference Example 18.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.6 Hz), 2.12-2.64 (11H, m), 2.91 (2H,t, J=7.0 Hz), 3.36 (1H, q, J=6.6 Hz), 3.70 (2H, q, J=6.6 Hz), 6.11 (1H,br), 7.10-7.30 (4H, m), 7.55 (4H, s-like).

melting point: 110-112° C. (ethyl acetate-isopropyl ether)

EXAMPLE 874′-chloro-N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamineobtained in Reference Example 18.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.6 Hz), 2.20-2.66 (11H, m), 2.93 (2H,t, J=6.8 Hz), 3.36 (1H, q, J=6.6 Hz), 3.73 (2H, q, J=6.6 Hz), 6.15 (1H,br), 7.18 (2H, d, J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz), 7.42 (2H, d, J=8.8Hz), 7.52 (2H, d, J=8.8 Hz), 7.58 (2H, d, J=8.5 Hz), 7.75 (2H, d, J=8.5Hz).

melting point: 151-152° C. (ethyl acetate-isopropyl ether)

EXAMPLE 884′-fluoro-N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamineobtained in Reference Example 18.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=7.0 Hz), 2.17-2.63 (11H, m), 2.93 (2H,t, J=7.0 Hz), 3.36 (1H, q, J=7.0 Hz), 3.73 (2H, q, J=6.4 Hz), 6.16 (1H,br), 7.08-7.32 (6H, m), 7.48-7.64 (4H, m), 7.76 (2H, d, J=8.4 Hz).

melting point: 134-135° C. (ethyl acetate-isopropyl ether)

EXAMPLE 89N-(2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethyl)-4′-(trifluoromethoxy)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using2-{4-[1-(4-methyl-1-piperazinyl)ethyl]phenyl}ethylamine obtained inReference Example 18.

¹H-NMR (CDCl₃) δ: 1.36 (3H, d, J=6.6 Hz), 2.15-2.65 (11H, m), 2.94 (2H,t, J=6.8 Hz), 3.37 (1H, q, J=6.6 Hz), 3.74 (2H, q, J=6.5 Hz), 6.17 (1H,br), 7.13-7.36 (6H, m), 7.54-7.68 (4H, m), 7.78 (2H, d, J=8.4 Hz).

melting point: 140-143° C. (ethyl acetate-isopropyl ether)

EXAMPLE 904′-chloro-3-fluoro-N-(2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethylamine obtained inReference Example 7.

¹H-NMR (CDCl₃) δ: 2.28 (3H, s), 2.46 (8H, m), 2.93 (2H, t, J=7.1 Hz),3.49 (2H, s), 3.74 (2H, m), 6.75 (1H, m), 7.19 (2H, d, J=8.1 Hz), 7.27(3H, m), 7.43 (3H, m), 7.51 (2H, m), 8.15 (1H, t, J=8.3 Hz).

melting point: 116-117° C. (ethyl acetate-isopropyl ether)

EXAMPLE 914′-fluoro-N-(2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylaminedihydrochloride obtained in Reference Example 11.

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=6.1 Hz), 1.46 (1H, m), 1.67 (2H, m),1.94 (1H, m), 2.10 (1H, q, J=9.0 Hz), 2.38 (1H, m), 2.88 (1H, d, J=2.7Hz), 2.93 (2H, t, J=6.7 Hz), 3.12 (1H, d, J=12.7 Hz), 3.73 (2H, m), 3.99(1H, d, J=12.9 Hz), 6.12 (1H, m), 7.13 (2H, m), 7.18 (2H, d, J=8.3 Hz),7.28 (2H, m), 7.55 (4H, m), 7.74 (2H, d, J=8.6 Hz).

melting point: 172-173° C. (ethyl acetate-isopropyl ether)

EXAMPLE 924′-chloro-N-(2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylaminedihydrochloride obtained in Reference Example 11.

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=5.9 Hz), 1.45 (1H, m), 1.67 (2H, m),1.94 (1H, m), 2.10 (1H, q, J=8.8 Hz), 2.38 (1H, m), 2.88 (1H, m), 2.93(2H, t, J=6.8 Hz), 3.11 (1H, d, J=12.9 Hz), 3.73 (2H, m), 3.99 (1H, d,J=12.7 Hz), 6.13 (1H, t, J=5.5 Hz), 7.18 (2H, d, J=8.1 Hz), 7.28 (2H,m), 7.41 (2H, d, J=8.9 Hz), 7.51 (2H, d, J=8.9 Hz), 7.57 (2H, d, J=8.6Hz), 7.74 (2H, d, J=8.5 Hz).

melting point: 176-177° C. (ethyl acetate-isopropyl ether)

EXAMPLE 934′-chloro-3-fluoro-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-piperidinylmethyl)phenyl]ethylaminedihydrochloride obtained in Reference Example 6.

¹H-NMR (CDCl₃) δ: 1.43 (2H, m), 1.57 (4H, m), 2.36 (4H, m), 2.94 (2H, t,J=7.0 Hz), 3.45 (2H, s), 3.75 (2H, m), 6.79 (1H, m), 7.20 (2H, d, J=8.3Hz), 7.26 (3H, m), 7.44 (3H, m), 7.52 (2H, m), 8.16 (1H, t, J=8.3 Hz).

melting point: 134° C. (ethyl acetate-isopropyl ether)

EXAMPLE 944-(4-methyl-2-oxopentyl)-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 0.88 (6H, d, J=6.8 Hz), 1.79 (4H, m), 2.14 (1H, m)2.33 (2H, d, J=6.7 Hz), 2.52 (4H, m), 2.91 (2H, t, J=7.0 Hz), 3.60 (2H,s), 3.71 (4H, m), 6.08 (1H, t, J=5.8 Hz), 7.18 (2H, d, J=7.9 Hz), 7.23(2H, d, J=8.3 Hz), 7.29 (2H, m), 7.64 (2H, d, J=8.3 Hz).

melting point: 137-138° C. (ethyl acetate-isopropyl ether)

EXAMPLE 952-fluoro-4-(3-methyl-2-oxobutyl)-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 1.13 (6H, d, J=6.8 Hz), 1.79 (4H, m), 2.50 (4H, m),2.71 (1H, m), 2.91 (2H, t, J=7.1 Hz), 3.59 (2H, s), 3.72 (2H, m), 3.77(2H, s), 6.72 (1H, m), 6.95 (1H, dd, J=12.8, 1.5 Hz), 7.06 (1H, dd,J=8.1, 1.7 Hz), 7.18 (2H, d, J=8.3 Hz), 7.28 (2H, m), 8.03 (1H, t, J=8.1Hz).

melting point: 98-99° C. (ethyl acetate-isopropyl ether)

EXAMPLE 964-cyclopropylmethoxy-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 0.36 (2H, m), 0.66 (2H, m), 1.27 (1H, m), 1.78 (4H,m), 2.50 (4H, m), 2.90 (2H, t, J=6.8 Hz), 3.59 (2H, s), 3.69 (2H, m),3.82 (2H, d, J=6.8 Hz), 6.01 (1H, t, J=5.6 Hz), 6.88 (2H, d, J=9.4 Hz),7.17 (2H, d, J=8.1 Hz), 7.28 (2H, m), 7.62 (2H, m).

melting point: 136-137° C. (ethyl acetate-isopropyl ether)

EXAMPLE 974′-methoxy-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 1.78 (4H, m), 2.51 (4H, m), 2.93 (2H, t, J=6.8 Hz),3.60 (2H, s), 3.73 (2H, m), 3.85 (3H, s), 6.13 (1H, t, J=6.1 Hz), 6.98(2H, d, J=9.4 Hz), 7.19 (2H, d, J=8.1 Hz), 7.29 (2H, m), 7.55 (4H, m),7.72 (2H, d, J=8.6 Hz).

melting point: 184-185° C. (ethyl acetate-isopropyl ether)

EXAMPLE 983-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}-4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamineobtained in Reference Example 4.

¹H-NMR (CDCl₃) δ: 1.78 (4H, m), 2.50 (4H, m), 2.94 (2H, t, J=7.0 Hz),3.59 (2H, s), 3.76 (2H, m), 6.78 (1H, m), 7.20 (2H, d, J=8.1 Hz), 7.30(3H, m), 7.48 (1H, dd, J=8.2, 1.8 Hz), 7.70 (4H, m), 8.18 (1H, t, J=8.2Hz).

melting point: 139° C. (ethyl acetate-isopropyl ether)

EXAMPLE 993-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}-4′-(trifluoromethoxy)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamineobtained in Reference Example 4.

¹H-NMR (CDCl₃) δ: 1.78 (⁴H, m), 2.50 (4H, m), 2.94 (2H, t, J=7.0 Hz),3.59 (2H, s), 3.75 (2H, m), 6.78 (1H, m), 7.19 (2H, d, J=8.3 Hz), 7.28(5H, m), 7.44 (1H, dd, J=8.3, 1.7 Hz), 7.59 (2H, m), 8.16 (1H, t, J=8.2Hz).

melting point: 131-132° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1003-fluoro-4′-methoxy-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamineobtained in Reference Example 4.

¹H-NMR (CDCl₃) δ: 1.78 (4H, m), 2.51 (4H, m), 2.93 (2H, t, J=7.0 Hz),3.60 (2H, s), 3.75 (2H, m), 3.86 (3H, s), 6.79 (1H, m), 6.99 (2H, m),7.25 (5H, m), 7.44 (1H, dd, J=8.3, 1.7 Hz), 7.54 (2H, m), 8.13 (1H, t,J=8.3 Hz).

melting point: 149° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1013-fluoro-4′-methyl-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamineobtained in Reference Example 4.

¹H-NMR (CDCl₃) δ: 1.78 (4H, m), 2.40 (3H, s), 2.50 (4H, m), 2.93 (2H, t,J=7.0 Hz), 3.59 (2H, s), 3.74 (2H, m), 6.78 (1H, m), 7.19 (2H, d, J=8.1Hz), 7.28 (5H, m), 7.47 (3H, m), 8.12 (1H, t, J=8.3 Hz).

melting point: 147-148° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1023-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamineobtained in Reference Example 4.

¹H-NMR (CDCl₃) δ: 1.79 (4H, m), 2.50 (4H, m), 2.94 (2H, t, J=7.0 Hz),3.59 (2H, s), 3.76 (2H, m), 6.79 (1H, m), 7.20 (2H, d, J=8.1 Hz), 7.29(3H, m), 7.44 (4H, m), 7.58 (2H, m), 8.15 (1H, t, J=8.3 Hz).

melting point: 134-135° C. (ethyl acetate-isopropyl ether)

EXAMPLE 103N-{2-[4-(1-pyrrolidinylthyl)phenyl]ethyl}-4′-(trifluoromethoxy)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by similar operations as in Example 2and Example 6 and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamineobtained in Reference Example 4.

¹H-NMR (CDCl₃) δ: 1.78 (4H, m), 2.51 (4H, m), 2.94 (2H, t, J=6.8 Hz),3.60 (2H, s), 3.74 (2H, m), 6.13 (1H, t, J=6.2 Hz), 7.19 (2H, d, J=8.1Hz), 7.28 (4H, m), 7.59 (4H, m), 7.75 (2H, d, J=8.6 Hz).

melting point: 181-183° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1044′-methyl-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 1.79 (4H, m), 2.40 (3H, s), 2.51 (4H, m), 2.94 (2H, t,J=6.8 Hz), 3.60 (2H, s), 3.74 (2H, m), 6.13 (1H, t, J=5.8 Hz), 7.20 (2H,d, J=7.9 Hz), 7.27 (2H, d, J=7.9 Hz), 7.30 (2H, m), 7.51 (2H, m), 7.61(2H, m), 7.74 (2H, m).

melting point: 176-178° C. (ethyl acetate-isopropyl ether)

EXAMPLE 105N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 1.78 (4H, m), 2.51 (4H, m), 2.94 (2H, t, J=6.9 Hz),3.60 (2H, s), 3.74 (2H, m), 6.15 (1H, t, J=5.5 Hz), 7.20 (2H, d, J=7.9Hz), 7.30 (2H, m), 7.42 (3H, m), 7.61 (4H, m), 7.76 (2H, m).

melting point: 169-171° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1064-cyclopropylmethoxy-N-(2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylaminedihydrochloride obtained in Reference Example 11.

¹H-NMR (CDCl₃) δ: 0.35 (2H, m), 0.66 (2H, m), 1.17 (3H, d, J=6.1 Hz),1.27 (1H, m), 1.45 (1H, m), 1.68 (2H, m), 1.94 (1H, m), 2.09 (1H, m),2.38 (1H, m), 2.90 (3H, m), 3.11 (1H, d, J=12.9 Hz), 3.68 (2H, m), 3.82(2H, d, J=6.8 Hz), 3.99 (1H, d, J=12.7 Hz), 6.00 (1H, t, J=5.4 Hz), 6.87(2H, d, J=9.4 Hz), 7.16 (2H, d, J=8.1 Hz), 7.27 (2H, m), 7.62 (2H, d,J=9.4 Hz).

melting point: 116-118° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1074-benzyloxy-N-(2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylaminedihydrochloride obtained in Reference Example 11.

¹H-NMR (CDCl₃) δ: 1.17 (3H, d, J=6.1 Hz), 1.46 (1H, m), 1.66 (2H, m),1.94 (1H, m), 2.09 (1H, m), 2.38 (1H, m), 2.90 (3H, m), 3.11 (1H, d,J=12.7 Hz), 3.69 (2H, m), 3.99 (1H, d, J=12.9 Hz), 5.09 (2H, s), 6.00(1H, t, J=6.1 Hz), 6.96 (2H, d, J=9.4 Hz), 7.16 (2H, d, J=8.1 Hz), 7.27(2H, m), 7.37 (5H, m), 7.63 (2H, m).

melting point: 129-131° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1082-fluoro-4-(3-methylbutoxy)-N-(2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylaminedihydrochloride obtained in Reference Example 11.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.16 (3H, d, J=6.0 Hz), 1.45(1H, m), 1.65 (2H, m), 1.68 (2H, m), 1.81 (1H, m), 1.94 (1H, m), 2.09(1H, m), 2.37 (1H, m), 2.89 (3H, m), 3.12 (1H, d, J=12.8 Hz), 3.71 (2H,m), 4.00 (3H, m), 6.56 (1H, dd, J=14.3, 2.5 Hz), 6.68 (1H, m), 6.76 (1H,dd, J=8.9, 2.5 Hz), 7.18 (2H, d, J=8.1 Hz), 7.27 (2H, m), 8.03 (1H, t,J=9.1 Hz).

melting point: 70-74° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1094′-chloro-N-[2-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethyl][1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 2and using2-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethylaminedihydrochloride obtained in Reference Example 8.

¹H-NMR (CDCl₃) δ: 1.08 (6H, d, J=6.2 Hz), 1.44 (6H, m), 2.49 (2H, m),2.93 (2H, t, J=6.8 Hz), 3.74 (4H, m) 6.13 (1H, m), 7.17 (2H, d, J=8.1Hz), 7.35 (2H, m), 7.43 (2H, m), 7.55 (4H, m), 7.75 (2H, d, J=8.5 Hz).

melting point: 157-158° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1104-(2-cyclopropylethoxy)-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 0.12 (2H, m), 0.49 (2H, m), 0.84 (1H, m), 1.68 (2H, q,J=6.7 Hz), 1.78 (4H, m), 2.50 (4H, m), 2.90 (2H, t, J=6.8 Hz), 3.59 (2H,s), 3.69 (2H, m), 4.05 (2H, t, J=6.7 Hz), 6.03 (1H, t, J=5.9 Hz), 6.88(2H, d, J=9.3 Hz), 7.17 (2H, d, J=8.1 Hz), 7.28 (2H, m), 7.63 (2H, d,J=9.4 Hz).

melting point: 129° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1114-isobutoxy-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.78 (4H, m), 2.09 (1H, m),2.50 (4H, m), 2.90 (2H, t, J=6.8 Hz), 3.59 (2H, s), 3.69 (2H, m), 3.74(2H, d, J=6.6 Hz), 6.01 (1H, t, J=5.8 Hz), 6.87 (2H, d, J=9.3 Hz), 7.17(2H, d, J=8.1 Hz), 7.28 (2H, m), 7.62 (2H, m).

melting point: 120° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1124-(3-methylbutoxy)-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.68 (2H, q, J=6.9 Hz), 1.81(5H, m), 2.50 (4H, m), 2.90 (2H, t, J=6.8 Hz), 3.59 (2H, s), 3.69 (2H,m), 4.01 (2H, m), 6.00 (1H, t, J=5.5 Hz), 6.87 (2H, m), 7.17 (2H, d,J=8.1 Hz), 7.28 (2H, m), 7.62 (2H, m).

melting point: 106° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1134-(2-cyclopropylethoxy)-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-piperidinylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 6.

¹H-NMR (CDCl₃) δ: 0.12 (2H, m), 0.49 (2H, m), 0.84 (1H, m), 1.43 (2H,m), 1.57 (4H, m), 1.68 (2H, q, J=6.8 Hz), 2.36 (4H, m), 2.90 (2H, t,J=6.8 Hz), 3.44 (2H, s), 3.69 (2H, m), 4.05 (2H, m), 6.01 (1H, t, J=5.6Hz), 6.88 (2H, m), 7.16 (2H, d, J=7.8 Hz), 7.26 (2H, m), 7.63 (2H, m).

melting point: 143° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1144-isobutoxy-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-piperidinylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 6.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.43 (2H, m), 1.57 (4H, m),2.09 (1H, m), 2.36 (4H, m), 2.90 (2H, t, J=6.8 Hz), 3.44 (2H, s), 3.69(2H, m), 3.74 (2H, d, J=6.6 Hz), 6.00 (1H, t, J=5.9 Hz), 6.87 (2H, d,J=9.3 Hz), 7.16 (2H, d, J=8.1 Hz), 7.26 (2H, m), 7.62 (2H, m).

melting point: 139° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1154-(3-methylbutoxy)-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-piperidinylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 6.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.44 (2H, m), 1.57 (4H, m),1.68 (2H, q, J=6.7 Hz), 1.83 (1H, m), 2.36 (4H, m), 2.90 (2H, t, J=6.8Hz), 3.44 (2H, s), 3.69 (2H, m), 4.01 (2H, m), 6.00 (1H, t, J=5.8 Hz),6.87 (2H, d, J=9.3 Hz), 7.16 (2H, d, J=8.1 Hz), 7.26 (2H, m), 7.62 (2H,d, J=9.3 Hz).

melting point: 135° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1164-benzyloxy-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-piperidinylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 6.

¹H-NMR (CDCl₃) δ: 1.43 (2H, m), 1.57 (4H, m), 2.36 (4H, m), 2.90 (2H, t,J=6.8 Hz), 3.44 (2H, s), 3.69 (2H, m), 5.09 (2H, s), 6.00 (1H, m), 6.96(2H, d, J=9.3 Hz), 7.16 (2H, d, J=8.3 Hz), 7.26 (2H, m), 7.36 (5H, m),7.63 (2H, d, J=9.4 Hz).

melting point: 137-138° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1174-(cyclopropylmethoxy)-N-{2-[4-(1-piperidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-piperidinylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 6.

¹H-NMR (CDCl₃) δ: 0.36 (2H, m), 0.66 (2H, m), 1.27 (1H, m), 1.43 (2H,m), 1.57 (4H, m), 2.37 (4H, m), 2.90 (2H, t, J=6.7 Hz), 3.44 (2H, s),3.69 (2H, m), 3.82 (2H, d, J=6.8 Hz), 6.00 (1H, t, J=6.0 Hz), 6.88 (2H,d, J=9.3 Hz), 7.16 (2H, d, J=8.1 Hz), 7.26 (2H, m), 7.62 (2H, d, J=9.3Hz).

melting point: 154° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1184-(2-cyclopropylethoxy)-N-(2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylaminedihydrochloride obtained in Reference Example 11.

¹H-NMR (CDCl₃) δ: 0.12 (2H, m), 0.49 (2H, m), 0.85 (1H, m), 1.17 (3H, d,J=6.1 Hz), 1.45 (1H, m), 1.66 (4H, m), 1.94 (1H, m), 2.09 (1H, q, J=9.0Hz), 2.38 (1H, m), 2.90 (3H, m), 3.11 (1H, d, J=12.9 Hz), 3.69 (2H, m),3.99 (1H, d, J=12.7 Hz), 4.06 (2H, m), 5.99 (1H, m), 6.88 (2H, m), 7.17(2H, d, J=7.8 Hz), 7.27 (2H, m), 7.62 (2H, m).

melting point: 115-116° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1194-isobutoxy-N-(2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylaminedihydrochloride obtained in Reference Example 11.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 1.16 (3H, d, J=5.9 Hz), 1.46(1H, m), 1.66 (2H, m), 1.94 (1H, m), 2.09 (2H, m), 2.38 (1H, m), 2.90(3H, m), 3.11 (1H, d, J=12.9 Hz), 3.69 (2H, m), 3.74 (2H, d, J=6.6 Hz),3.99 (1H, d, J=12.7 Hz), 5.99 (1H, t, J=5.0 Hz), 6.87 (2H, d, J=9.3 Hz),7.16 (2H, d, J=8.3 Hz), 7.27 (2H, m), 7.62 (2H, m).

melting point: 105° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1204-(3-methylbutoxy)-N-(2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylaminedihydrochloride obtained in Reference Example 11.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.17 (3H, d, J=6.0 Hz), 1.45(1H, m), 1.69 (4H, m), 1.83 (1H, m), 1.94 (1H, m), 2.10 (1H, q, J=9.0Hz), 2.37 (1H, m), 2.90 (3H, m), 3.12 (1H, d, J=12.6 Hz), 3.70 (2H, m),4.00 (3H, m), 6.00 (1H, t, J=5.6 Hz), 6.88 (2H, m), 7.17 (2H, d, J=8.1Hz), 7.28 (2H, m), 7.63 (2H, m).

melting point: 91-93° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1214-benzyloxy-N-(2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethylaminetrihydrochloride obtained in Reference Example 7.

¹H-NMR (CDCl₃) δ: 2.28 (3H, s), 2.46 (8H, m), 2.90 (2H, t, J=6.8 Hz),3.49 (2H, s), 3.69 (2H, m), 5.10 (2H, s), 6.02 (1H, t, J=5.6 Hz), 6.97(2H, d, J=9.3 Hz), 7.18 (2H, d, J=7.9 Hz), 7.27 (2H, m), 7.38 (5H, m),7.65 (2H, m).

melting point: 143-144° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1224-cyclopropylmethoxy-N-(2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethylaminetrihydrochloride obtained in Reference Example 7.

¹H-NMR (CDCl₃) δ: 0.36 (2H, m), 0.66 (2H, m), 1.28 (1H, m), 2.28 (3H,s), 2.46 (8H, m), 2.90 (2H, t, J=6.8 Hz), 3.49 (2H, s), 3.69 (2H, m),3.83 (2H, d, J=6.7 Hz), 6.02 (1H, t, J=5.5 Hz), 6.89 (2H, m), 7.18 (2H,d, J=7.9 Hz), 7.27 (2H, m), 7.64 (2H, d, J=9.4 Hz).

melting point: 162° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1234-(2-cyclopropylethoxy)-N-(2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethylaminetrihydrochloride obtained in Reference Example 7.

¹H-NMR (CDCl₃) δ: 0.12 (2H, m), 0.49 (2H, m), 0.84 (1H, m), 1.69 (2H, q,J=6.8 Hz), 2.29 (3H, s), 2.46 (8H, m), 2.91 (2H, t, J=6.8 Hz), 3.50 (2H,s), 3.69 (2H, m), 4.06 (2H, t, J=6.8 Hz), 6.03 (1H, t, J=5.6 Hz), 6.90(2H, d, J=9.3 Hz), 7.18 (2H, d, J=7.9 Hz), 7.28 (2H, m), 7.64 (2H, m).

melting point: 132-133° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1244-isobutoxy-N-(2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethylaminetrihydrochloride obtained in Reference Example 7.

¹H-NMR (CDCl₃) δ: 1.03 (6H, d, J=6.8 Hz), 2.09 (1H, m), 2.28 (3H, s),2.47 (8H, m), 2.91 (2H, t, J=7.0 Hz), 3.49 (2H, s), 3.69 (2H, m), 3.74(2H, d, J=6.4 Hz), 6.03 (1H, t, J=5.5 Hz), 6.88 (2H, d, J=9.3 Hz), 7.18(2H, d, J=7.9 Hz), 7.28 (2H, m), 7.64 (2H, m).

melting point: 130° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1254-(3-methylbutoxy)-N-(2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}ethylaminetrihydrochloride obtained in Reference Example 7.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.4 Hz), 1.68 (2H, q, J=6.7 Hz), 1.83(1H, m), 2.28 (3H, s), 2.46 (8H, m), 2.90 (2H, t, J=7.0 Hz), 3.49 (2H,s), 3.69 (2H, m), 4.01 (2H, m), 6.02 (1H, t, J=5.5 Hz), 6.88 (2H, m),7.18 (2H, d, J=7.9 Hz), 7.28 (2H, m), 7.64 (2H, m).

melting point: 117° C. (ethyl acetate-isopropyl ether)

EXAMPLE 126N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(benzyloxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-azepanylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 9.

¹H-NMR (CDCl₃) δ: 1.62 (8H, m), 2.62 (4H, m), 2.90 (2H, t, J=6.9 Hz),3.62 (2H, s), 3.70 (2H, m), 5.10 (2H, s), 6.01 (1H, t, J=5.5 Hz), 6.97(2H, m), 7.17 (2H, d, J=8.1 Hz), 7.30 (2H, d, J=8.1 Hz), 7.38 (5H, m),7.64 (2H, m).

melting point: 116-120° C. (ethyl acetate-isopropyl ether)

EXAMPLE 127N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(cyclopropylmethoxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-azepanylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 9.

¹H-NMR (CDCl₃) δ: 0.35 (2H, m), 0.66 (2H, m), 1.27 (1H, m), 1.62 (8H,m), 2.62 (4H, m), 2.90 (2H, t, J=6.9 Hz), 3.62 (2H, s), 3.69 (2H, m),3.83 (2H, m), 6.01 (1H, t, J=6.0 Hz), 6.89 (2H, m), 7.17 (2H, d, J=7.9Hz), 7.30 (2H, m), 7.63 (2H, m).

melting point: 122-123° C. (ethyl acetate-isopropyl ether)

EXAMPLE 128N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(2-cyclopropylethoxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-azepanylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 9.

¹H-NMR (CDCl₃) δ: 0.12 (2H, m), 0.49 (2H, m), 0.84 (1H, m), 1.62 (8H,m), 1.69 (2H, q, J=6.8 Hz), 2.63 (4H, m), 2.91 (2H, t, J=6.8 Hz), 3.62(2H, s), 3.70 (2H, m), 4.06 (2H, t, J=6.8 Hz), 6.03 (1H, t, J=5.4 Hz),6.89 (2H, m), 7.17 (2H, d, J=8.1 Hz), 7.30 (2H, m), 7.63 (2H, m).

melting point: 112° C. (ethyl acetate-isopropyl ether)

EXAMPLE 129N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(isobutoxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-azepanylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 9.

¹H-NMR (CDCl₃) δ: 1.02 (6H, d, J=6.8 Hz), 1.62 (8H, m), 2.09 (1H, m),2.63 (4H, m), 2.90 (2H, t, J=6.9 Hz), 3.62 (2H, s), 3.70 (2H, m), 3.74(2H, d, J=6.6 Hz), 6.01 (1H, t, J=5.5 Hz), 6.88 (2H, m), 7.17 (2H, d,J=7.9 Hz), 7.30 (2H, m), 7.63 (2H, m).

melting point: 104-106° C. (ethyl acetate-isopropyl ether)

EXAMPLE 130N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(3-methylbutoxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-azepanylmethyl)phenyl]ethylamine dihydrochlorideobtained in Reference Example 9.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.62 (8H, m), 1.68 (2H, m),1.83 (1H, m), 2.63 (4H, m), 2.90 (2H, t, J=6.9 Hz), 3.62 (2H, s), 3.69(2H, m), 4.01 (2H, t, J=7.0 Hz), 6.03 (1H, t, J=5.6 Hz), 6.88 (2H, m),7.17 (2H, d, J=8.1 Hz), 7.30 (2H, m), 7.63 (2H, m).

melting point: 107-108° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1314-benzyloxy-N-[2-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethyl]benzamide

The title compound was obtained by a similar operation as in Example 2and using2-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethylaminedihydrochloride obtained in Reference Example 8.

¹H-NMR (CDCl₃) δ: 1.08 (6H, d, J=6.2 Hz), 1.49 (6H, m), 2.48 (2H, m),2.90 (2H, t, J=6.9 Hz), 3.70 (2H, q, J=6.7 Hz), 3.80 (2H, s), 5.10 (2H,s), 6.00 (1H, t, J=5.0 Hz), 6.96 (2H, d, J=8.7 Hz), 7.15 (2H, d, J=8.1Hz), 7.37 (7H, m), 7.64 (2H, d, J=8.7 Hz).

melting point: 124° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1324-cyclopropylmethoxy-N-[2-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethyl]benzamide

The title compound was obtained by a similar operation as in Example 2and using2-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethylaminedihydrochloride obtained in Reference Example 8.

¹H-NMR (CDCl₃) δ: 0.36 (2H, m), 0.66 (2H, m), 1.08 (6H, d, J=6.2 Hz),1.28 (4H, m), 1.60 (3H, m), 2.49 (2H, m), 2.90 (2H, t, J=6.8 Hz), 3.69(2H, m), 3.79 (2H, s), 3.83 (2H, m), 6.01 (1H, t, J=4.52 Hz), 6.88 (2H,d, J=8.85 Hz), 7.15 (2H, d, J=8.1 Hz), 7.33 (2H, d, J=7.9 Hz), 7.63 (2H,d, J=8.85 Hz).

melting point: 141-142° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1334-(2-cyclopropylethoxy)-N-[2-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethyl]benzamide

The title compound was obtained by a similar operation as in Example 2and using2-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethylaminedihydrochloride obtained in Reference Example 8.

¹H-NMR (CDCl₃) δ: 0.12 (2H, m), 0.49 (2H, m), 0.85 (1H, m), 1.08 (6H, d,J=6.2 Hz), 1.31 (3H, m), 1.58 (3H, m), 1.69 (2H, q, J=6.8 Hz), 2.48 (2H,m), 2.90 (2H, t, J=6.9 Hz), 3.70 (2H, m), 3.80 (2H, s), 4.06 (2H, t,J=6.8 Hz), 6.02 (1H, t, J=5.3 Hz), 6.89 (2H, m), 7.16 (2H, d, J=8.1 Hz),7.34 (2H, d, J=8.3 Hz), 7.63 (2H, m).

melting point: 99-102° C. (ethyl acetate-isopropyl ether)

EXAMPLE 134N-[2-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethyl]-4-(isopentyloxy)benzamide

The title compound was obtained by a similar operation as in Example 2and using2-(4-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]methyl}phenyl)ethylaminedihydrochloride obtained in Reference Example 8.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.08 (6H, d, J=6.2 Hz), 1.29(3H, m), 1.58 (3H, m), 1.68 (2H, q, J=6.7 Hz), 1.82 (1H, m), 2.49 (2H,m), 2.90 (2H, t, J=6.9 Hz), 3.69 (2H, m), 3.80 (2H, s), 4.01 (2H, t,J=6.7 Hz), 6.02 (1H, t, J=5.4 Hz), 6.88 (2H, m), 7.15 (2H, d, J=8.1 Hz),7.34 (2H, d, J=8.1 Hz), 7.63 (2H, m).

melting point: 108° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1354′-chloro-N-(2-{4-[2-(diethylamino)ethoxy]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

To a solution of4′-chloro-N-[2-(4-methoxyphenyl)ethyl][1,1′-biphenyl]-4-carboxamide (700mg, 1.91 mmol) obtained in Reference Example 22 in dichloromethane (10ml) was added dropwise 1.0 mol/l solution (4.21 ml, 4.21 mmol) of borontribromide in dichloroethane at 0° C., and the mixture was stirred atroom temperature for 15 hrs. Water was added to the reaction mixture,and the mixture was extracted with ethyl acetate, and the extract wasdried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure to give a demethylated compound (620 mg). A solution of4′-chloro-N-[2-(4-hydroxyphenyl)ethyl][1,1′-biphenyl]-4-carboxamide (620mg), N-(2-chloroethyl)-N,N-diethylamine hydrochloride (364 mg, 2.11mmol) and potassium carbonate (876 mg, 6.34 mmol) in dimethylformamide(10 ml) was stirred at room temperature for 6 hrs and at 100° C. for 4days. Ethyl acetate was added to the reaction mixture, and the mixturewas washed with 1N aqueous sodium hydroxide solution and brine, anddried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure, and the obtained residue was purified by NH-silicacolumn chromatography (developing solvent; chloroform:ethylacetate:hexane=1:1:2), and powderized with isopropyl ether to give thetitle compound (318 mg).

¹H-NMR (CDCl₃) δ: 1.07 (6H, t, J=7.2 Hz), 2.64 (4H, q, J=7.2 Hz), 2.88(4H, m), 3.71 (2H, m), 4.04 (2H, t, J=6.5 Hz), 6.12 (1H, t, J=6.1 Hz),6.88 (2H, d, J=9.1 Hz), 7.15 (2H, m), 7.43 (2H, d, J=8.8 Hz), 7.53 (2H,d, J=8.9Hz), 7.59 (2H, d, J=8.6 Hz), 7.76 (2H, d, J=8.5 Hz).

melting point: 178-179° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1364-bromo-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}benzamide

A solution of4-bromo-N-{2-[4-(cyclopropylcarbonyl)phenyl]ethyl}benzamide (3.00 g,8.06 mmol) obtained in Reference Example 24 and magnesium chloride (76.7mg, 0.806 mmol) in methylformamide (2.83 ml, 48.4 mmol) was stirred at200° C. for 1 day. Aqueous potassium carbonate solution was added to thereaction mixture. The mixture was extracted with ethyl acetate, and theextract was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure, and theobtained residue was purified by NH-silica gel column chromatography(developing solvent; ethyl acetate), and powderized with isopropyl etherto give the title compound (1.86 g).

¹H-NMR (DMSO-d₆) δ: 1.57 (1H, m), 1.78 (2H, m), 2.04 (3H, s), 2.08-2.24(2H, m), 2.81 (2H, m), 2.98 (1H, m), 3.12 (1H, m), 3.45 (2H, m), 7.16(2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.66 (2H, d, J=8.7 Hz), 7.76(2H, d, J=8.7 Hz), 8.65 (1H, t, J=5.7 Hz).

melting point: 133-134° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1374′-chloro-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}benzamide obtainedin Example 136.

¹H-NMR (DMSO-d₆) δ: 1.57 (1H, m), 1.78 (2H, m), 2.04 (3H, s), 2.09-2.24(2H, m), 2.84 (2H, m), 2.99 (1H, m), 3.13 (1H, m), 3.49 (2H, m), 7.23(4H, m), 7.55 (2H, d, J=8.7 Hz), 7.77 (4H, m), 7.93 (2H, d, J=8.4 Hz),8.68 (1H, t, J=5.4 Hz).

melting point: 169-171° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 419 [M+H]⁺

EXAMPLE 1384-cyclopropylmethoxy-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethylamine obtained inReference Example 25.

¹H-NMR (DMSO-d₆) δ: 0.33 (2H, m), 0.57 (2H, m), 1.23 (1H, m), 1.57 (1H,m), 1.69-1.85 (2H, m), 2.04 (3H, s), 2.08-2.24 (2H, m), 2.80 (2H, m),2.99 (1H, m), 3.13 (1H, m), 3.44 (2H, m), 3.86 (2H, d, J=6.9 Hz), 6.97(2H, d, J=8.7 Hz), 7.17 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz), 7.79(2H, d, J=8.7 Hz), 8.43 (1H, t, J=5.4 Hz).

melting point: 143-145° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 379 [M+H]⁺

EXAMPLE 1394′-methoxy-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 6and using4-bromo-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}benzamide obtainedin Example 136.

¹H-NMR (DMSO-d₆) δ: 1.55 (1H, m), 1.76 (2H, m), 2.05 (3H, s), 2.09-2.22(2H, m), 2.84 (2H, m), 3.00 (1H, m), 3.13 (1H, m), 3.49 (2H, m), 3.81(3H, s), 7.05 (2H, d, J=8.7 Hz), 7.18-7.27 (4H, m), 7.67-7.73 (4H, m),7.89 (2H, d, J=8.4 Hz), 8.61 (1H, t, J=5.7 Hz).

melting point: 165-167° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 415 [M+H]⁺

EXAMPLE 1404-cyclopropylmethoxy-2-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (DMSO-d₆) δ: 0.31 (2H, m), 0.55 (2H, m), 1.20 (1H, m), 1.64 (4H,m), 2.38 (4H, m), 2.77 (2H, m), 3.42 (2H, m), 3.50 (2H, s), 3.85 (2H, d,J=7.2 Hz), 6.78-6.86 (2H, m), 7.15 (2H, d, J=8.4 Hz), 7.20 (2H, d, J=8.4Hz), 7.55 (1H, t, J=9.0 Hz), 8.07 (1H, m).

melting point: 90-92° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 397 [M+H]⁺

EXAMPLE 1414-(2-cyclopropylethoxy)-2-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-[4-(1-pyrrolidinylmethyl)phenyl]ethylamine obtained inReference Example 4.

¹H-NMR (DMSO-d₆) δ: 0.12 (2H, m), 0.42 (2H, m), 0.80 (1H, m), 1.60 (2H,m), 1.65 (4H, m), 2.39 (4H, m), 2.78 (2H, m), 3.42 (2H, m), 3.51 (2H,s), 4.06 (2H, d, J=6.6 Hz), 6.80-6.88 (2H, m), 7.16 (2H, d, J=8.4 Hz),7.21 (2H, d, J=8.4 Hz), 7.56 (1H, t, J=9.0 Hz), 8.08 (1H, m).

melting point: 66-68° C. (ethyl acetate-isopropyl ether)

FABMS (pos) 411 [M+H]⁺

EXAMPLE 1424′-chloro-N-(2-{4-[(2-methyl-4,5-dihydro-1H-imidazol-1-yl)methyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

tert-Butyl(2-{4-[(2-methyl-4,5-dihydro-1H-imidazol-1-yl)methyl]phenyl}ethyl)carbamatewas obtained by a similar operation as in Reference Example 3 and usingmethyl 4-{2-[(tert-butoxycarbonyl)amino]ethyl}benzoate obtained inReference Example 2.(2-{4-[(2-Methyl-4,5-dihydro-1H-imidazol-1-yl)methyl]phenyl}ethyl)aminehydrochloride was obtained by a similar operation as in ReferenceExample 4 and using this compound. The title compound was obtained by asimilar operation as in Example 2 and using this compound.

¹H-NMR (CDCl₃) δ: 2.08 (3H, s), 2.96 (2H, t, J=7.1 Hz), 3.28 (2H, t,J=9.9 Hz), 3.68-3.77 (4H, m), 4.31 (2H, s), 6.30 (1H, m), 7.19 (2H, d,J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz), 7.43 (2H, d, J=8.4 Hz), 7.53 (2H, d,J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 7.79 (2H, d, J=8.4 Hz), 8.02 (1H, s).

melting point: 170-172° C. (isopropyl ether)

EXAMPLE 1434-(3-methylbutoxy)-N-(2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 2and using 2-{4-[(2-methyl-1-pyrrolidinyl)methyl]phenyl}ethylaminedihydrochloride obtained in Reference Example 11.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 1.17 (3H, d, J=6.1 Hz),1.38-1.53 (2H, m), 1.60-1.68 (1H, m), 1.64-1.72 (2H, m), 1.78-1.98 (2H,m), 2.09 (1H, q, J=9.0 Hz), 2.33-2.41 (1H, m), 2.86-2.94 (3H, m), 3.11(1H, d, J=12.7 Hz), 3.65-3.73 (2H, m), 3.96-4.04 (3H, m), 5.99 (1H, s),6.84-6.90 (2H, m), 7.14-7.19 (2H, m), 7.25-7.30 2H, m), 7.59-7.65 (2H,m).

melting point: 91-93° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1444-cyclopropylmethoxy-2-fluoro-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)benzamide

To a solution of 4-(cyclopropylmethoxy)-2-fluorobenzoic acid (242 mg,1.15 mmol) and dimethylformamide (1 drop) in tetrahydrofuran (3 ml) wasadded dropwise oxalyl dichloride (113 μl, 1.30 mmol) at 0° C., and themixture was stirred at room temperature for 30 min. The reaction mixturewas concentrated under reduced pressure and the obtained residue wasdissolved in tetrahydrofuran (3 ml). The solution was added dropwise toa solution of 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine (310 mg,1.02 mmol) obtained in Reference Example 15 and triethylamine (558 μl,4.00 mmol) in tetrahydrofuran (2 ml) at 0° C., and the mixture wasstirred at room temperature for 3 hrs. Water was added to the reactionmixture. The mixture was extracted with ethyl acetate, and the extractwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure, and theobtained residue was purified by NH-silica gel column chromatography(developing solvent; ethyl acetate) to give the title compound (200 mg).

¹H-NMR (CDCl₃) δ: 0.36 (2H, m), 0.66 (2H, m), 1.24 (1H, m), 1.34 (2H,m), 1.36 (3H, d, J=6.6 Hz), 1.55 (4H, m), 2.35 (4H, m), 2.90 (2H, t,J=6.0 Hz), 3.39 (1H, q, J=6.9 Hz), 3.71 (2H, q, J=6.9 Hz), 3.82 (2H, d,J=6.9 Hz), 6.53 (1H, d, J=14.4 Hz), 6.54 (1H, m),), 6.76 (1H, d, J=8.7Hz), 7.16 (2H, d, J=8.1 Hz), 7.24 (2H, d, J=8.1 Hz), 8.03 (1H, t, J=9.3Hz).

EXAMPLE 1454-(2-cyclopropylethoxy)-2-fluoro-N-(2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 144and using 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine obtained inReference Example 15.

¹H-NMR (CDCl₃) δ: 0.02 (2H, m), 0.38 (2H, m), 0.72 (1H, m), 1.24 (2H,m), 1.26 (3H, d, J=6.6 Hz), 1.44 (4H, m), 1.56 (2H, q, J=6.6 Hz), 2.23(4H, m), 2.79 (2H, t, J=7.2 Hz), 3.27 (1H, q, J=6.6 Hz), 3.59 (2H, q,J=6.3 Hz), 3.82 (2H, d, J=6.6 Hz), 6.42 (1H, d, J=14.4 Hz), 6.48 (1H,m), 6.64 (1H, d, J=8.7 Hz), 7.05 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1Hz), 7.91 (1H, t, J=9.3 Hz).

EXAMPLE 1464-cyclopropylmethoxy-N-methyl-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 144and using N-methyl-2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 26.

¹H-NMR (CDCl₃) δ: 0.36 (2H, m), 0.63 (2H, m), 1.22 (1H, m), 1.42 (3H, d,J=6.6 Hz), 1.78 (4H, m), 2.45 (2H, m), 2.45 (2H, m), 2.57 (2H, m), 2.86(3H, m), 2.95 (1H, m), 3.19 (1H, m), 3.44 (1H, m), 3.78 (4H, m),6.81-6.89 (2H, m), 6.94 (1H, m), 7.12 (1H, m), 7.15 (2H, m), 7.33 (2H,m).

EXAMPLE 147N-methyl-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide

The title compound was obtained by a similar operation as in Example 144and using N-methyl-2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamineobtained in Reference Example 26.

¹H-NMR (CDCl₃) δ: 1.41 (3H, d, J=6.1 Hz), 1.75 (4H, m), 2.37 (2H, m),2.55 (2H, m), 2.86 (3H, m), 2.98 (1H, m), 3.15 (2H, m), 3.52 (1H, m),3.79 (1H, m), 6.93 (1H, m), 7.13 (1H, m), 7.24-7.62 (11H, m).

EXAMPLE 1484-(2-cyclopropylethoxy)-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 144and using 2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine obtained inReference Example 14.

¹H-NMR (CDCl₃) δ: 0.96 (2H, m), 0.48 (2H, m), 0.84 (1H, m), 1.41 (3H, d,J=6.6 Hz), 1.64 (2H, m), 1.76 (4H, m), 2.35 (2H, m), 2.54 (2H, m), 2.90(2H, t, J=6.9 Hz), 3.16 (1H, q, J=6.3 Hz), 3.69 (2H, q, J=6.6 Hz), 4.05(2H, t, J=6.6 Hz), 6.02 (1H, m), 6.87 (2H, d, J=9.0 Hz), 7.16 (2H, d,J=8.1 Hz), 7.27 (2H, d, J=9.0 Hz), 7.63 (2H, d, J=9.0 Hz).

melting point: 102-103° C. (ethyl acetate-isopropyl ether)

EXAMPLE 1494-(3-methylbutoxy)-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide

The title compound was obtained by a similar operation as in Example 144and using 2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethylamine obtained inReference Example 14.

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=6.2 Hz), 1.39 (3H, d, J=6.2 Hz), 7.76(6H, m), 2.37 (2H, m), 2.54 (2H, m), 2.90 (2H, t, J=6.6 Hz), 3.16 (1H,q, J=6.3 Hz), 3.68 (2H, q, J=6.0 Hz), 4.01 (2H, t, J=6.6 Hz), 6.02 (1H,m), 6.87 (2H, d, J=8.4 Hz), 7.16 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=9.0Hz), 7.62 (2H, d, J=8.6 Hz).

melting point: 103-104° C. (ethyl acetate-isopropyl ether)

FORMULATION EXAMPLE 1

(1) compound obtained in Example 8 50 mg (2) lactose 34 mg (3)cornstarch 10.6 mg   (4) cornstarch (paste)  5 mg (5) magnesium stearate0.4 mg  (6) carboxymethyl cellulose calcium 20 mg total 120 mg 

According to conventional methods, the above-mentioned (1)-(6) weremixed and punched by a tableting machine to give tablets.

EXPERIMENTAL EXAMPLE 1 Determination of Antagonistic Activity of TestCompound Using GTP γ S Binding Assay

Using human SLC-1 expression CHO cell clone 57 and rat SLC-1 expressionCHO cell clone 44 described in WO01/82925, SLC-1 expression CHO cellmembrane fractions were prepared by the following method. In phosphatebuffered saline (pH 7.4) supplemented with 5 mM EDTA (ethylenediaminetetraacetic acid) were suspended human and rat SLC-1 expression CHOcells (1×10⁸) and centrifuged. Homogenate buffer (10 ml, 10 mM NaHCO₃, 5mM EDTA, pH 7.5) was added to the pellets of the cells and, usingPolytron Homogeniser, the mixture was homogenated. The supernatantobtained after centrifugation at 400×g for 15 min was furthercentrifuged at 100,000×g for 1 hr to give precipitate of the membranefraction. The precipitate was suspended in 2 ml of an assay buffer [50mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.1% BSA (bovine serum albumin), 10 mMMgCl₂, 100 mM NaCl, 1 μM GDP (guanosine 5′-diphosphate), 0.25 mM PMSF(phenylmethylsulfonylfluoride), 1 mg/ml pepstatin, 20 mg/ml leupeptin,10 mg/ml phosphoramidon] and centrifuged at 100,000×g for 1 hr. Themembrane fraction recovered as precipitate was suspended again in 20 mlof an assay buffer, and after dispensing, preserved at −80° C. and usedupon thawing each time when in use.

The antagonistic activity of the test compound was determined asfollows. The SLC-1 expression CHO cell membrane fraction (171 μl)diluted with an assay buffer was dispensed to a polypropylene 96 wellplate and 3×10⁻¹⁰ M MCH (2 μl) diluted with DMSO solution, test compoundsolution (2 μl) diluted to various concentrations and[³⁵S]-Guanosine5′-(γ-thio)triphosphate (25 μl, Daiichi Pure ChemicalsCo., Ltd.) were respectively added (cell membrane final concentration:20 μg/ml, [³⁵S]-Guanosine 5′-(γ-thio)triphosphate final concentration:0.33 nM). The reaction mixture was reacted at 25° C. for 1 hr withstirring, suction filtered with a glass filter (GF-C) and washed 3 timeswith a wash solution (300 μl, 50 mM Tris-HCl buffer, pH 7.5). Liquidscintillator (50 ml) was added to the glass filter and the residualradioactivity was determined by a liquid scintillation counter.Binding inhibition (%)=(radioactivity upon addition of test compound andMCH−radioactivity upon addition of DMSO solution)/(radioactivity uponaddition of MCH−radioactivity upon addition of DMSO solution)×100

From the binding inhibition (%), IC₅₀ of the test compound wascalculated. The results are shown in the following. Compound No.Inhibitory activity (IC₅₀: nM) Example 67 3

INDUSTRIAL APPLICABILITY

The compound of the present invention has a superior MCH receptorantagonistic action and is useful as an agent for the prophylaxis ortreatment of obesity and the like.

1. A compound represented by the formula:

wherein Ar¹ is a cyclic group optionally having substituent(s); R is a hydrogen atom, an optionally halogenated C₁₋₆ alkyl, a phenyl optionally having substituent(s) or a pyridyl optionally having substituent(s); Ra¹, Ra², Ra³ and Ra⁴ are the same or different and each is a hydrogen atom, an optionally halogenated C₁₋₆ alkyl, a phenyl optionally having substituent(s), a halogen atom, a pyridyl optionally having substituent(s), a cyano, an optionally halogenated C₁₋₆ alkoxy, an optionally halogenated C₁₋₆ alkylthio, an amino, a mono- or di-C₁₋₆ alkylamino, a formyl, an optionally halogenated C₁₋₆ alkyl-carbonyl or an optionally halogenated C₁₋₆ alkylsulfonyl; Ar is a monocyclic aromatic ring optionally having substituent(s); Y is an optionally halogenated alkylene group; and R¹ and R² are (1) the same or different and each is a hydrogen atom or a C₁₋₆ alkyl, (2) R¹ and R² form a nitrogen-containing heterocycle optionally having substituent(s) together with the adjacent nitrogen atom, or (3) R¹ and Y form a nitrogen-containing heterocycle optionally having substituent(s) together with the adjacent nitrogen atom, and R² is a hydrogen atom or a C₁₋₆ alkyl; provided that when the nitrogen-containing heterocycle formed by R¹ and R² together with the adjacent nitrogen atom is a piperazine, or when R is a C₁₋₄ alkyl, Ar¹ is a cyclic group having substituent(s), or a salt thereof.
 2. The compound of claim 1, wherein R¹ and R² are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl, or R¹ and R² form a nitrogen-containing heterocycle optionally having substituent(s) together with the adjacent nitrogen atom.
 3. The compound of claim 1, wherein Ar¹ is a group represented by the formula: Ar³—Ar²— (wherein Ar² is a cyclic group optionally having substituent(s) and Ar³ is an aromatic group optionally having substituent(s)).
 4. The compound of claim 1, wherein R is a hydrogen atom.
 5. The compound of claim 1, wherein Ra¹, Ra², Ra³ and Ra⁴ are each a hydrogen atom.
 6. The compound of claim 1, wherein Ar is a benzene ring.
 7. The compound of claim 1, wherein Y is a C₁₋₆ alkylene group.
 8. The compound of claim 1, wherein R¹ and R² form a nitrogen-containing heterocycle optionally having substituent(s) together with the adjacent nitrogen atom.
 9. The compound of claim 8, wherein the nitrogen-containing heterocycle is a piperidine, a pyrrolidine, a hexamethylenimine, a morpholine or a thiomorpholine.
 10. The compound of claim 1, which is 4′-chloro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide; 4′-chloro-3-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide; 4′-chloro-N-(2-{4-[1-(1-pyrrolidinyl)propyl]phenyl}ethyl)[1,1′-biphenyl]-4-carboxamide; 4-(cyclopropylmethoxy)-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide; 4-methoxy-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide; N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(cyclopropylmethoxy)benzamide; N-{2-[4-(1-azepanylmethyl)phenyl]ethyl}-4-(2-cyclopropylethoxy)benzamide; 4′-chloro-N-{2-[4-(1-methyl-2-pyrrolidinyl)phenyl]ethyl}[1,1′-biphenyl]-4-carboxamide; or 4-(2-cyclopropylethoxy)-N-(2-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}ethyl)benzamide.
 11. A pharmaceutical agent which comprises the compound of claim 1 or a salt thereof or a prodrug thereof.
 12. The pharmaceutical agent of claim 11, which is a melanin-concentrating hormone antagonist.
 13. The pharmaceutical agent of claim 11, which is an agent for the prophylaxis or treatment of a disease caused by a melanin-concentrating hormone.
 14. The pharmaceutical agent of claim 11, which is an agent for the prophylaxis or treatment of obesity.
 15. The pharmaceutical agent of claim 11, which is a feeding deterrent.
 16. The pharmaceutical agent of claim 11, which is an agent for the prophylaxis or treatment of depression.
 17. The pharmaceutical agent of claim 11, which is an agent for the prophylaxis or treatment of anxiety.
 18. (canceled)
 19. A method for antagonizing a melanin-concentrating hormone receptor in a mammal, which comprises administering an effective amount of the compound of claim 1 or a salt thereof or a prodrug thereof to said mammal.
 20. A method for for the production of an agent for the prophylaxis or treatment of a disease caused by a melanin-concentrating hormone said method comprising formulating a pharmaceutical composition with the compound of claim 1 or a salt thereof or a prodrug thereof and a pharmaceutically acceptable carrier, excipient or diluent.
 21. A method for preventing or treating a disease caused by a melanin-concentrating hormone in a mammal, which comprises administering an effective amount of the compound of claim 1 or a salt thereof or a prodrug thereof to said mammal.
 22. The method of claim 20 for the production of an agent for the prophylaxis or treatment of obesity.
 23. A method for preventing or treating obesity in a mammal, which comprises administering an effective amount of the compound of claim 1 or a salt thereof or a prodrug thereof to said mammal.
 24. The method of claim 20 for the production of a feeding deterrent.
 25. A method for suppressing food intake by a mammal, which comprises administering an effective amount of the compound of claim 1 or a salt thereof or a prodrug thereof to said mammal.
 26. The method of claim 20 for the production of an agent for the prophylaxis or treatment of depression.
 27. A method for preventing or treating depression in a mammal, which comprises administering an effective amount of the compound of claim 1 or a salt thereof or a prodrug thereof to said mammal.
 28. The method of claim 20 for the production of an agent for the prophylaxis or treatment of anxiety.
 29. A method for preventing or treating anxiety in a mammal, which comprises administering an effective amount of the compound of claim 1 or a salt thereof or a prodrug thereof to said mammal. 